JPH0971558A - Production of aromatic amido compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially advantageously obtain an aromatic amido compound useful as an intermediate of a medicine at a high yield by significantly simplifying operations such as post-treatments in every reaction process. SOLUTION: This aromatic amido compound is expressed by formula I, e.g. 3-(4-(4-phenyl-1-butoxy)-benzoyl)amino-2-hydroxy-acetophenone. The compound of the formula I is obtained by reacting a benzoic ester of formula II (R is an alkyl), e.g. an alky p-hydroxybenzoate with a haloalkylbenzene of formula III (X<1> is a halogen), e.g. a 4-phenyl-1-halobutane in the presence of a basic substance and an aprotic polar compound, e.g. dimethyl sulfoxide in an aromatic hydrocarbon-based solvent to obtain an ether, hydrolyzing with an alkali in the presence of water, precipitating by an acid to obtain a benzoic acid, reacting the benzoic acid with a halogenating agent to obtain an acid halide, then reacting the acid halide with an aromatic amine.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an industrially advantageous method for producing an aromatic amide compound represented by the following formula (7) which is useful as a pharmaceutical intermediate.

[0002]

2. Description of the Related Art Japanese Unexamined Patent Publication No. 3-95144 discloses p-
A process for producing 2-acetyl-6- [4- (4-phenylbutoxy) benzoyl] aminophenol using oxybenzoic acid ester, 1-halogeno-4-phenylbutane and acetylaminophenols is described. However, the yield of the target substance in the more specifically described examples is not always sufficient, and it is difficult to say that the operating conditions in each step are necessarily satisfactory as an industrial production method, and further improvement is required. Was wanted.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to develop a more industrially advantageous method for producing an aromatic amide compound represented by the following formula (7).

As a result of intensive studies for solving the above problems, the present inventors have found that 2-acetyl-6- [4] using p-oxybenzoic acid ester, 1-halogeno-4-phenylbutane and acetylaminophenols. In the method for producing-(4-phenylbutoxy) benzoyl] aminophenol, the following formula (3) is carried out in the presence of a basic compound by unifying the solvent in each step with an aromatic hydrocarbon solvent.
It was found that not only the target compound can be obtained in a high yield by coexisting a specific compound in the step of producing an ether shown by, but also the operation such as post-treatment in each step can be greatly simplified. Came to.

That is, the present invention has the general formula (1) (In the formula, R represents an optionally branched lower alkyl group.) And a benzoic acid ester represented by the general formula (2). (Wherein X ¹ represents a halogen atom) is reacted with an aromatic hydrocarbon solvent in the presence of a basic substance and an aprotic polar compound to give a compound of the general formula (3) (Wherein R represents the same meaning as described above), ethers in the aromatic hydrocarbon solvent are hydrolyzed with an alkali in the presence of water, and then subjected to acid precipitation. Formula (4) The benzoic acid represented by the formula (5) is obtained by reacting a benzoic acid in an aromatic hydrocarbon solvent with a halogenating agent. (In the formula, X ² represents a halogen atom.), And the acid halide in the aromatic hydrocarbon solvent and the formula (6) are obtained. Represented by the formula (7) characterized by reacting with an aromatic amine The present invention provides a method for producing an aromatic amide compound represented by and a method for producing an intermediate thereof. The aromatic amide compound (7) obtained in the present invention is disclosed in, for example, JP-A-3-
A compound represented by the following formula can be obtained by the method described in Japanese Patent Publication No. 95144, and the compound is useful as a therapeutic agent for various allergic diseases.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below. [Ethers (4) Production Step] By reacting benzoic acid esters (1) and haloalkylbenzene (2) in the presence of a basic substance and an aprotic polar compound in an aromatic hydrocarbon solvent, Ethers (3) are obtained. Specific examples of R in benzoic acid esters (1) and ethers (3) include lower branched alkyl groups such as methyl, ethyl, propyl, butyl, and pentyl which may be branched. Examples of X ¹ of the haloalkylbenzene (2) include halogen atoms such as chlorine, bromine and iodine.

Examples of the aromatic hydrocarbon solvent used in the present invention include solvents mainly composed of aromatic hydrocarbons such as benzene, toluene, xylene, monochlorobenzene and dichlorobenzene. In terms of industrial operability, it is more preferable to use the same type of solvent as a unified solvent. The amount of such a solvent to be used is generally 1 to 10 times by weight, preferably 1 to 10 times, the amount of the haloalkylbenzene (2).
5 times the weight. Examples of the basic substance include hydrides of alkali metals such as sodium hydride, potassium hydride and calcium hydride, alkaline earth metals; lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, and hydroxide. Alkali metals such as barium, hydroxides of alkaline earth metals, iron hydroxides; alkali metals such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, carbonates of alkaline earth metals; sodium hydrogen carbonate Examples thereof include alkali metal hydrogencarbonates such as potassium hydrogencarbonate, and preferably alkali metal and alkaline earth metal carbonates. The amount of the basic substance is usually 1 to 5 with respect to the benzoic acid ester (1).
It is a molar ratio, preferably 1 to 3 molar times.

In this step, an aprotic polar compound is allowed to coexist with the above basic substance,
The reaction rate can be significantly accelerated. Examples of such aprotic polar compound include sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, and the like.
Amides such as N-methyl-2-pyrrolidone, nitriles such as acetonitrile, formamides such as N, N-dimethylformamide, phosphorylamides such as hexamethylphosphoric triamide, acetone, methyl ethyl ketone, methyl isobutyl ketone, etc. Examples include ethers such as ketones, tetrahydrofuran, ethylene glycol dimethyl ether, and polyethylene glycol. Preferred are dimethyl sulfoxide, sulfolane and N-methyl-2-pyrrolidone. Also, these are
Two or more types may be used in combination. From the viewpoint of reaction rate, the amount of such aprotic polar compound used is usually 0.1 mol times or more, preferably 0.2 mol times or more, and more preferably 0.4 mol times or more with respect to the haloalkylbenzene (2). The molar ratio is not less than 5 times, and usually about not more than 5 times, preferably about 3 times from the viewpoint of the liquid separation property between the organic layer and the aqueous layer in the case of performing post-treatment or washing with water as necessary in the subsequent steps. Hereafter, it is more preferably about 2 mol times or less.

The upper limit of the reaction temperature of this reaction may be determined by the boiling point of the solvent used, but it is usually from -50 to 15
It is in the range of 0 ° C, preferably -30 to 110 ° C. The reaction time is not particularly limited, and the reaction can be terminated when the benzoic acid ester (2) or the haloalkylbenzene (3) disappears.

After completion of the reaction, the obtained reaction mixture can be used as it is in the next reaction, but usually, the basic compound, the salt formed, and the aprotic polar compound are obtained by washing the reaction mixture with water. Etc. are removed before use in the next reaction. The ethers (3) are usually subjected to the next step as a solution of an aromatic hydrocarbon solvent without isolation, but they can also be isolated.

[Production Process of Benzoic Acids (4)] Ethers (3) in the aromatic hydrocarbon solvent obtained in the above process
Is hydrolyzed with alkali in the presence of water, and then subjected to acid precipitation to obtain benzoic acids (4). Examples of the alkali to be used include inorganic bases such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide. The amount of the alkali used is usually 1 equivalent or more with respect to the ether (3). The water used is usually added in the form of an aqueous solution of said alkali. The amount of water is usually 0.2 to 1 with respect to ethers (3).
It is 0 times by weight, preferably 0.5 to 5 times by weight.

In this step, addition of alcohols such as methanol, ethanol and propanol is preferred because the reaction is significantly promoted. The amount of such alcohols is usually about 0.1 to 5 times the weight of the ethers (3).

The upper limit of the reaction temperature of this reaction may be determined by the boiling point of the solvent used, but the reaction temperature is usually-
It is in the range of 30 to 200 ° C, preferably -20 to 150 ° C. The reaction time is not particularly limited, and ethers (3)
The reaction can be terminated by disappearance of. Also,
When alcohols are added, the hydrolysis reaction may be allowed to proceed while the alcohol is distilled off, or the alcohols may be distilled off after the hydrolysis. Of course, it is also possible to use for the next step without distilling off the alcohols. The salt of the benzoic acid (4) produced here is sulfuric acid,
The aqueous layer is extracted by acidifying the aqueous layer by addition of hydrochloric acid or the like, and is usually subjected to dehydration treatment such as azeotropic treatment and dehydrating agent treatment, and then the benzoic acid (4) aromatic hydrocarbon solvent solution Used in the process, it can also be isolated.

[Production Step of Acid Halide (5)] The acid halide (5) is obtained by reacting the benzoic acid (4) in the aromatic hydrocarbon solvent obtained above with a halogenating agent. Examples of X ² of the acid halide (5) include halogen atoms such as chlorine, bromine and iodine. A usual method is used for the acid halogenation reaction of the benzoic acids (4). Examples of the halogenating agent used in this reaction include thionyl chloride, thionyl bromide, sulfuryl chloride, and other thionyl halides, sulfuryl halides; phosphorus pentachloride, phosphorus trichloride, phosphorus pentabromide, phosphorus tribromide, and triiodide. Examples thereof include phosphorus halides such as phosphorus, phosgene compounds such as phosgene, diphosgene, triphosgene, and the like. The amount of the halogenating agent used is usually 1 equivalent or more with respect to the benzoic acid (4).

For such an acid halogenation reaction, it is preferable to add a catalytic amount of an organic base. Examples of such an organic base include dimethylformamide and pyridines. As pyridines, in addition to unsubstituted pyridine,
Monoalkyl-substituted pyridines such as picoline, ethyl pyridine, propyl pyridine, butyl pyridine, tertiary butyl pyridine, 2,3-dimethyl pyridine,
2,4-dimethylpyridine, 2,5-dimethylpyridine, 2,6-dimethylpyridine, 3,5-dimethylpyridine, 2-methyl-5-ethylpyridine, 2,6-diisopropylpyridine, 2,6-ditertiary Dialkyl pyridines, such as butyl pyridine, are mentioned. The amount of the organic base added is usually 0.005 to 0.5 equivalent times, and preferably 0.1 to 0.5 times the amount of the benzoic acid (4).
It is 005 to 0.1 equivalent times.

The upper limit of the reaction temperature of this reaction may be determined by the boiling point of the solvent used, but the reaction temperature is usually
It is in the range of -80 to 150 ° C, preferably -30 to 100 ° C. The reaction time is not particularly limited, and benzoic acids (4)
The reaction can be terminated by disappearance of. The resulting aromatic hydrocarbon solvent solution of the acid halide (5) is, if necessary, removed by removing excess halogenating agent by distillation or the like, and then subjected to the next amidation without isolation as the acid halide (5). It is subjected to a reaction, but can also be isolated.

[Aromatic amide compound production step] Acid halide (5) in the aromatic hydrocarbon solvent obtained above
The aromatic amide compound (7) is obtained by reacting with the aromatic amine (6). The aromatic amine (6) used may be a free amine or an acid addition salt. In the present invention, the free amine or acid addition salt thereof may be simply referred to as an aromatic amine (6) for convenience. Examples of such acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, hydrobromide and hydroiodide, or acetate, lactate, tartrate, benzoate. Acid salt, citrate,
Methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate,
Examples thereof include organic acid salts such as glucuronic acid salts and gluconic acid salts. The amount of the aromatic amine (6) used is usually 0.2 to 5 mol times, preferably 0.5 to 2 mol times, relative to the acid halide (5).

The reaction of the acid halide (5) with the aromatic amine (6) is carried out by adding the aromatic amine (6) or its aromatic hydrocarbon solvent to the aromatic hydrocarbon solvent solution of the acid halide (5). Various methods such as a method of adding a liquid, a method of adding an aromatic hydrocarbon solvent solution of an acid halide (5) to an aromatic amine (6) or an aromatic hydrocarbon solvent solution thereof, a method of simultaneously adding both of them. The method can be adopted. In terms of suppressing side reactions, aromatic amine (6)
Alternatively, a method of adding the aromatic hydrocarbon solvent solution of the acid halide (5) to the aromatic hydrocarbon solvent solution and a method of simultaneously adding both are preferable.

In this reaction, a deoxidizing agent can be used if necessary. Examples of such deoxidizing agents include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide, and iron hydroxide. Iron group metal hydroxides such as lithium carbonate, sodium carbonate,
Examples thereof include alkali metal carbonates such as potassium carbonate, alkaline earth metal carbonates such as magnesium carbonate, calcium carbonate and barium carbonate, and alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. The use amount of the deoxidizing agent is usually 1 to 10 equivalent times, preferably 1 to 5 equivalent times with respect to the benzoic acid (4). When a deoxidizing agent is used, the reaction is usually carried out by adding an aromatic hydrocarbon solvent solution of an aromatic amine (6) to an aromatic hydrocarbon solvent solution of an acid halide (5) and a deoxidizing agent. It is done by doing. The deoxidizing agent may be added either before or after the addition of the acid halide (5), or may be simultaneous with the addition of the acid halide (5). It is also possible to use the deoxidizing agent in the form of an aqueous solution as long as the pH of the reaction system does not become too high. Specifically, for example, a method of maintaining the pH of the reaction system at 7 or less by pouring an acid halide (5) and an aqueous solution of a deoxidizing agent together,
A method of adding an aqueous solution of a deoxidizer after adding the acid halide (5) can be mentioned.

The upper limit of the reaction temperature of this reaction may be determined by the boiling point of the solvent used, but the reaction temperature is usually
-80 to 200 ° C, preferably -30 to 100
C., more preferably 30 to 60.degree. The reaction time is not particularly limited, and the reaction can be terminated when the acid halide (5) or the aromatic amine (6) disappears.

After the completion of the reaction, the aromatic amide compound (7) can be obtained in good yield by a usual separating means such as extraction, liquid separation, concentration and the like, and if necessary, it is purified by recrystallization or the like. You can also Alternatively, it may be used as a solution of an aromatic hydrocarbon solvent without performing an isolation operation such as concentration, for example, as an intermediate of a desired drug.

[0022]

INDUSTRIAL APPLICABILITY The aromatic amide compound (7) obtained in the present invention is a compound useful as a pharmaceutical intermediate, and the compound of the present invention can be produced in an excellent yield and industrially advantageously by the method of the present invention. be able to.

[0023]

The present invention will be described in more detail based on the following examples, but the invention is not intended to be limited to these examples. The completion of the reaction in each reaction was confirmed by the disappearance of any raw material by high performance liquid chromatography (area percentage method). Purity was measured by high performance liquid chromatography (internal standard method). However, all the acid halides (5) were derivatized with aniline and then analyzed.

Example 1 4-Phenyl-1-bromobutane (50.0 g),
Methyl p-hydroxybenzoate (39.3 g), anhydrous potassium carbonate (48.7 g), sulfolane (42.2 g)
Then, toluene (100 g) was charged, and the mixture was reacted at 95 ° C. for 9 hours. After the reaction was completed, the reaction mixture was washed with water, separated, and the aqueous layer was removed. Methanol (50 g) and 27% aqueous sodium hydroxide solution (82.0 g) were added, and the mixture was reacted under reflux (70 to 75 ° C) for 2 hours. . After the reaction was completed, sulfuric acid was added to acidify the aqueous layer, the aqueous layer was removed by liquid separation, and toluene was partially distilled off from the organic layer under heating to remove 4- (4-phenyl-1-butoxy) benzoic acid. Toluene solution (123.5g, purity 10
A 0% conversion amount of 62.4 g) was obtained. Net yield 98.4%.

A toluene solution of 4- (4-phenyl-1-butoxy) benzoic acid obtained above (92.8
Dimethylformamide (0.2 g) was added to 100 g (converted amount: 46.9 g of 100% purity), and the temperature was raised to 65 to 75 ° C. Thionyl chloride (22.5 g) was added dropwise to this solution in the same temperature range for 15 minutes and kept warm for 30 minutes. After the reaction was completed, thionyl chloride was distilled off under reduced pressure to give 4- (4-phenyl-).
Toluene solution of 1-butoxy) benzoyl chloride (7
9.3 g) was obtained. This toluene solution was used for the next reaction without purification.

Toluene (160 g) and 3-amino-
2-Hydroxyacetophenone (hereinafter abbreviated as AHA) sulfate (molecular weight 249.3, 42.3 g) was charged, and the temperature was raised to 40 ° C. To this solution at this temperature was added a toluene solution of 4- (4-phenyl-1-butoxy) benzoyl chloride obtained above (79.3 g) and an aqueous solution of sodium carbonate [4- (4-phenyl-1-butoxy).
1.6 equivalent times the amount of benzoic acid] was simultaneously added dropwise over 1 hour, and the temperature was kept at the same temperature for 2 hours. After completion of the reaction, the reaction mixture was neutralized with hydrochloric acid, the organic layer was washed with water and separated, then cooled to 0 ° C. and kept warm to crystallize 3- (4- (4
-Phenyl-1-butoxy) -benzoyl) -amino-
2-Hydroxy-acetophenone (66.8 g) was obtained. Net yield 97.3% (vs AHA / sulfate), purity 9
9.8%.

Example 2 4-Phenyl-1-bromobutane (30.1 g),
Methyl p-hydroxybenzoate (27.8 g), anhydrous potassium carbonate (29.1 g), dimethyl sulfoxide (1
1.0 g) and toluene (120 g) were charged, and the mixture was reacted under reflux (115 to 120 ° C.) for 6 hours. After the reaction,
After washing with water and separating the layers and removing the aqueous layer, methanol (30
g) and 27% aqueous sodium hydroxide solution (41.8 g) were added, and the mixture was reacted under reflux (70 to 75 ° C.) for 3 hours. After completion of the reaction, sulfuric acid was added to acidify the aqueous layer, the aqueous layer was removed by liquid separation, and toluene was partially distilled off from the organic layer under heating,
Toluene solution of 4- (4-phenyl-1-butoxy) benzoic acid (74.2 g, purity 100% conversion amount 37.1 g)
I got Net yield 97.2%.

A toluene solution of 4- (4-phenyl-1-butoxy) benzoic acid obtained above (46.6)
Dimethylformamide (0.1 g) was added to 100 g and a purity of 100% (23.3 g), and the temperature was raised to 65 to 75 ° C. Thionyl chloride (11.2 g) was added dropwise to this solution within the same temperature range for 15 minutes and kept warm for 30 minutes. After the reaction was completed, thionyl chloride was distilled off under reduced pressure to give 4- (4-phenyl-).
Toluene solution of 1-butoxy) benzoyl chloride (4
1.1 g) was obtained. This toluene solution was used for the next reaction without purification.

Toluene (80 g) and 3-amino-2
-Hydroxyacetophenone (AHA) · hydrochloride (molecular weight 187.6, 15.9 g) was charged and the temperature was raised to 40 ° C. To this solution at this temperature, the 4- (4
-Phenyl-1-butoxy) benzoyl chloride solution in toluene (41.1 g) and aqueous sodium carbonate solution [4-
For (4-phenyl-1-butoxy) benzoic acid, 1.
2 eq.] Was added dropwise over 1 hour at the same time, and the temperature was kept at the same temperature for 2 hours. After completion of the reaction, the reaction mixture was neutralized with hydrochloric acid, the organic layer was washed with water, separated, cooled to 0 ° C., kept warm and crystallized to give 3- (4- (4-phenyl-1-butoxy). ) -Benzoyl) -amino-2-hydroxy-acetophenone (33.4 g) was obtained. Net yield 96.9%
(Vs AHA / hydrochloride), purity 99.6%.

Example 3 4-Phenyl-1-bromobutane (30.0 g),
Methyl p-hydroxybenzoate (23.7 g), anhydrous potassium carbonate (29.3 g), dimethyl sulfoxide (5.5 g) and toluene (60 g) were charged, and the mixture was reacted under reflux (115 to 120 ° C.) for 6.5 hours. Let After the reaction was completed, the reaction mixture was washed with water, separated, and the aqueous layer was removed.
0.6 g), 27% aqueous sodium hydroxide solution (41.8
g) was added, and the mixture was reacted under reflux (70 to 75 ° C.) for 1 hour. After the reaction was completed, sulfuric acid was added to acidify the aqueous layer, the aqueous layer was removed by liquid separation, and toluene was partially distilled off from the organic layer.
A toluene solution of-(4-phenyl-1-butoxy) benzoic acid (73.8 g, purity 100% conversion amount 36.5 g) was obtained. Net yield 95.8%.

A toluene solution of 4- (4-phenyl-1-butoxy) benzoic acid obtained above (46.8)
Dimethylformamide (0.1 g) was added to 100 g and 100% purity converted amount of 23.1 g), and the temperature was raised to 65 to 75 ° C. Thionyl chloride (11.0 g) was added dropwise to this solution within the same temperature range for 15 minutes and kept warm for 30 minutes. After the reaction was completed, thionyl chloride was distilled off under reduced pressure to give 4- (4-phenyl-).
Toluene solution of 1-butoxy) benzoyl chloride (4
0.7 g) was obtained. This toluene solution was used for the next reaction without purification.

Toluene (80 g) and AHA / sulfate (21.3 g) were charged, and the temperature was raised to 40 ° C. To this solution at this temperature was added a toluene solution of 4- (4-phenyl-1-butoxy) benzoyl chloride (40.7 g) obtained above and an aqueous sodium carbonate solution [4- (4-phenyl-1-butoxy) benzoic acid. 1.6 equivalent times of acid] was simultaneously added dropwise over 1 hour, and the temperature was kept at the same temperature for 2 hours. After completion of the reaction, the reaction mixture was neutralized with hydrochloric acid, the organic layer was washed with water, separated, cooled to 0 ° C., kept warm and crystallized to give 3- (4- (4-phenyl-1-butoxy). )
-Benzoyl) -amino-2-hydroxy-acetophenone (33.6g) was obtained. Net yield 95.2% (vs. 4-
(4-phenyl-1-butoxy) benzoic acid), purity 9
8.5%.

Example 4 4-Phenyl-1-bromobutane (30.0 g),
Methyl p-hydroxybenzoate (27.7 g), anhydrous potassium carbonate (29.3 g), N-methyl-2-pyrrolidone (14 g) and toluene (120 g) were charged, and the mixture was refluxed (115 to 120 ° C.) for 10 hours. It was made to react. After completion of the reaction, the reaction mixture was washed with water, separated, and the aqueous layer was removed.
g) and 27% aqueous sodium hydroxide solution (41.9 g) were added, and the mixture was reacted under reflux (70 to 75 ° C.) for 3 hours. After completion of the reaction, sulfuric acid was added to acidify the aqueous layer, the aqueous layer was removed by liquid separation, and toluene was partially distilled off from the organic layer under heating,
Toluene solution of 4- (4-phenyl-1-butoxy) benzoic acid (76.0 g, purity 100% conversion amount 37.6 g)
I got Net yield 98.9%.

A toluene solution of 4- (4-phenyl-1-butoxy) benzoic acid obtained above (46.6)
Dimethylformamide (0.1 g) was added to 100 g and 100% purity converted amount of 23.1 g), and the temperature was raised to 65 to 75 ° C. Thionyl chloride (11.3 g) was added dropwise to this solution within the same temperature range for 15 minutes and kept warm for 30 minutes. After the reaction was completed, thionyl chloride was distilled off under reduced pressure to give 4- (4-phenyl-).
Toluene solution of 1-butoxy) benzoyl chloride (4
1.4 g) was obtained. This toluene solution was used for the next reaction without purification.

Toluene (80 g) and AHA · hydrochloride (16.0 g) were charged, and the temperature was raised to 40 ° C. To this solution at this temperature was added a solution of 4- (4-phenyl-1-butoxy) benzoyl chloride obtained in (2) in toluene (41.4 g) and aqueous sodium carbonate solution [4- (4-phenyl-1-butoxy). ) 1.3 equivalent times relative to benzoic acid] was added dropwise over 1 hour at the same time, and the mixture was kept at the same temperature for 2 hours. After completion of the reaction, the reaction mixture was neutralized with hydrochloric acid, the organic layer was washed with water, separated, cooled to 0 ° C., kept warm and crystallized to give 3- (4- (4-phenyl-1-butoxy). )
-Benzoyl) -amino-2-hydroxy-acetophenone (32.1 g) was obtained. Net yield 93.3% (vs. AH
A, hydrochloride), purity 99.1%.

Example 5 4-Phenyl-1-bromobutane (38.2 g),
Methyl p-hydroxybenzoate (29.9 g), anhydrous potassium carbonate (37.1 g), sulfolane (12.9 g)
And toluene (76.2 g) were charged, and the mixture was refluxed (115
The reaction was carried out for 8 hours. After completion of the reaction, wash with water,
After liquid separation and removal of the aqueous layer, methanol (19.1 g), 27
% Aqueous sodium hydroxide solution (39.6 g) was added, and the mixture was reacted under reflux (70 to 75 ° C.) for 1.5 hours. After completion of the reaction, sulfuric acid was added to acidify the aqueous layer, the aqueous layer was removed by liquid separation, and toluene was partially distilled off from the organic layer under heating.
A toluene solution of (4-phenyl-1-butoxy) benzoic acid (216.0 g, purity 100% conversion amount 47.3 g) was obtained. Net yield 97.6%.

A toluene solution of 4- (4-phenyl-1-butoxy) benzoic acid obtained above (216.0
Dimethylformamide (0.2 g) was added to 100 g (converted amount: 47.3 g, purity: 100%), and the temperature was raised to 65 to 75 ° C. Thionyl chloride (22.4 g) was added dropwise to this solution in the same temperature range over 15 minutes, and the mixture was kept warm for 1 hour. After the reaction was completed, thionyl chloride was distilled off under reduced pressure to give 4- (4-phenyl-).
Toluene solution of 1-butoxy) benzoyl chloride (1
46.5 g) was obtained. This toluene solution was used for the next reaction without purification.

Toluene (162.0 g) and AHA
Sulfate (43.3 g) was charged and the temperature was raised to 45 ° C.
To this solution at this temperature was added a solution of 4- (4-phenyl-1-butoxy) benzoyl chloride obtained above in toluene (146.5 g) and aqueous sodium carbonate solution (4-
For (4-phenyl-1-butoxy) benzoic acid, 1.
(6 equivalent times) was added dropwise at the same time over 1 hour, and the temperature was kept at the same temperature for 2 hours. After completion of the reaction, the reaction mixture was neutralized with sulfuric acid, the organic layer was washed with water, separated, cooled to 0 ° C., kept warm and crystallized to give 3- (4- (4-phenyl-1-). Butoxy) -benzoyl) -amino-2-hydroxy-acetophenone (68.8 g) was obtained. Net yield (total from the above steps) 96.7% (vs. 4- (4-phenyl-1-)
Butoxy) benzoic acid), purity 99.6%.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Koichi Murata 2-10-1 Tsukahara, Takatsuki City, Osaka Sumitomo Chemical Co., Ltd.

Claims (8)

[Claims] 1. A general formula (1) (In the formula, R represents an optionally branched lower alkyl group.) And a benzoic acid ester represented by the general formula (2). (Wherein X ¹ represents a halogen atom) is reacted with an aromatic hydrocarbon solvent in the presence of a basic substance and an aprotic polar compound to give a compound of the general formula (3) (Wherein R represents the same meaning as described above), ethers in the aromatic hydrocarbon solvent are hydrolyzed with an alkali in the presence of water, and then subjected to acid precipitation. Formula (4) The benzoic acid represented by the formula (5) is obtained by reacting a benzoic acid in an aromatic hydrocarbon solvent with a halogenating agent. (In the formula, X ² represents a halogen atom.), And the acid halide in the aromatic hydrocarbon solvent and the formula (6) are obtained. Represented by the formula (7) characterized by reacting with an aromatic amine A method for producing an aromatic amide compound represented by: 2. The production method according to claim 1, wherein the aromatic hydrocarbon solvents are of the same type. 3. The method according to claim 1, wherein the aprotic polar compound is dimethyl sulfoxide, sulfolane or N-methyl-2-pyrrolidone. 4. The method according to claim 1, wherein the aromatic hydrocarbon solvent containing ethers represented by the general formula (3) is washed with water and then hydrolyzed. . 5. The production method according to claim 1, wherein the hydrolysis is carried out in the presence of alcohols. 6. The reaction of the acid halide represented by the general formula (5) with the aromatic amine represented by the general formula (6) is carried out for 30 to 30 minutes.
The manufacturing method according to any one of claims 1 to 5, which is performed in a temperature range of 60 ° C. 7. A benzoic acid ester represented by the general formula (1) and a haloalkylbenzene represented by the general formula (2) are added to an aromatic hydrocarbon in the presence of a basic substance and an aprotic polar compound. A method for producing an ether represented by the above general formula (3), characterized by reacting in a system solvent. 8. The method according to claim 7, wherein the aprotic polar compound is dimethyl sulfoxide, sulfolane or N-methyl-2-pyrrolidone.