KR790001738B1 - Process for the preparation of bis-(benzumido)-benzenes - Google Patents

Abstract

Phenylene bis (benzamides) (I; z = bond, O, NH2,NHCO; R1 = straight or side chain lower alkyl ; R2, R3 = lower alkyl,oxalic acid, lower alkoxy, lower alkanoyl oxy, halogen) heving antiulcer activity, were prepd. by the reaction of (II) and (III) or their carboxylic functional derivs. Thus, 2-MeC6H4COC1 was reacted with 2,4-(H2N)2 C6H3O(CH2)3 NEt2 3HC1 in aq. THF and K2Co3 at room temp. to give 1-(3'-diethylaminopropoxy)-2,4-bis (2"-methy1 benzamide)-benzene.

Description

Manufacturing method of bis- (benzamido) -benzene derivative

The present invention is a general formula

기를 의미하고, R₁은 직쇄상 혹은 측쇄상의 저급알킬렌기, R₂및 R₃는 각각 동일해도 상이해도 좋은 저급알킬기를 의미하고, 그외 R₂와 R₃는 직접으로 또는 이중원자를 개입하여 결합해 있어도 좋으며, R₄는 저급알킬기를 의미하고, 그외 R₄와 R₂혹은 R₃와 결합해 있어도 좋으며, Y 및 Z는 동일해도 상이해도 좋고, 수소원자, 저급알킬기, 수산기, 저급알콕시기, 저급알카노일옥시기 또는 할로겐원자를 의미함)으로 표시되는 비스－(벤즈아미도)－벤젠유도체의 제법에 관한 것이다.Wherein X is a direct bond or an oxygen atom, a -CONH- group or

R ₁ is a linear or branched lower alkylene group, R ₂ and R ₃ are each the same or different lower alkyl groups, and R ₂ and R ₃ are bonded directly or through a double atom. R ₄ may be a lower alkyl group, may be combined with other R ₄ and R ₂ or R ₃ , Y and Z may be the same or different, a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, And a bis- (benzamido) -benzene derivative represented by a lower alkanoyloxy group or a halogen atom.

According to this invention, the compound of the said general formula (I) is a general formula

Wherein X, R ₁ , R ₂ and R ₃ have the meaning of electricity

The compound represented by the general formula

(Where Y and Z have the meaning of electricity)

It is manufactured by making it react with the functional derivative in the compound represented by this, or its carboxyl group, and performing hydrolysis of an ester group or alkanoylation of a phenolic hydroxyl group in a product as needed.

The compound of general formula (I) obtained by the present invention is a novel compound and is useful as a medicine having a prophylactic and therapeutic effect on various experimental gastric ulcers, peripheral circulation improvement, blood pressure lowering effect, analgesic effect, etc. in experimental animals. Do.

The compound of formula (II) used in the present invention can be easily produced by, for example, reducing the corresponding dinitro body by a conventional method. The compound of formula (II) can also be used as an acid addition salt, for example, hydrochloride.

As a functional derivative of the compound of Formula (III), an acid halide, ester, anhydride, or mixed acid anhydride with carbonic acid, sulfuric acid, phosphoric acid, sulfonic acid, etc. are used, for example.

In carrying out the present invention, a conventional amide formation reaction is suitably used, for example, the functional derivative of the compound of formula (II) or its acid addition salt and the compound of formula (III) is usually -10 to 50 캜, preferably Condensation reaction is carried out at the temperature of 0-10 degreeC below. At this time, for example, water, benzene, toluene, tetrahydrofuran, ether, dioxane, dimethylformamide, chloroform, methylene chloride, acetonitrile, and mixtures thereof are used as the solvent. As a condensation adjuvant, inorganic bases, such as hydroxide, carbonate, and acetate of an alkylli metal or an alkyl earth metal, or organic bases, such as pyridine and triethylamine, are used, for example.

Furthermore, after activating the amino group of the compound of formula (II) with phosphorus trichloride, chloroamine acid ester or the like, the compound of formula (III) may be reacted at room temperature to the exchange temperature of the solvent. In this case, the reaction is carried out in a neutral solvent such as benzene, toluene, xylene, dioxane, tetrahydrofuran or a basic solvent such as pyridine. When the reaction is carried out in a neutral solvent, it is preferable to use a tertiary amine basic aid.

In addition, the compound of formula (II) and the compound of formula (III) may be condensed at once from room temperature to reflux temperature of the solvent in an inert solvent in the presence of an amide forming aid such as dicyclohexyl carbodiimide. As an inert solvent, tetrahydrofuran, chloroform, dioxane, acetonitrile, dimethylformamide, etc. are used, for example.

Usually, the functional derivative in the compound of Formula (III) or its carboxyl group is used in the ratio of 2-6 times equivalent, Preferably it is 2.2-4 times equivalent with respect to the compound of Formula (II).

In this way, the compound of formula (I) is obtained as a free base or an acid addition salt. When the product has an ester group, the ester group is hydrolyzed, and when the product has a phenolic hydroxyl group, this may be lower alkanoylated. These reactions are performed by a conventional method. Hydrolysis of an ester group is performed by making it react at room temperature-100 degreeC for 0.5 to 30 hours using aqueous solution, such as hydroxide, carbonate, of an alkali metal or alkaline-earth metal, for example. Further, lower alkanoylation of the phenolic hydroxyl group is performed by, for example, reacting the lower fatty acid acid chloride or acid anhydride at 0 to 100 ° C for 1 to 10 hours. Although the solvent at this time does not need to use especially, Inert solvent, such as tetrahydrofuran, dioxane, acetone, chloroform, may be used, for example.

Next, an Example is given and this invention is demonstrated concretely.

Example 1

14 g of 2-methylbenzoyl chloride was added immediately after 25 g of potassium carbonate, 50 ml of water, and 130 ml of tetrahydrofuran were added 10.4 g of 1- (3'-diethylaminopropoxy) -2,4-diaminobenzenetrichloride in ice-stirring. Add all at once, stop cooling and stir at room temperature for 3 hours. After completion of the reaction, the mixture was extracted with benzene, the basic material was collected in the water layer with dilute hydrochloric acid from the organic layer (if the hydrochloride is difficult to dissolve in water, it is dissolved using a small amount of methanol) and the water layer is washed with benzene and then potassium carbonate. The mixture was adjusted to pH 9 to 10, extracted with benzene again, washed with benzene layer, dried over potassium carbonate and concentrated. The residue was purified by silica gel column chromatography (eluted with benzene-methanol mixed solvent) and recrystallized with benzene-hexane mixed solvent to give 1- (3'-diethylaminopropoxy) -2,4-bis (2 9.9 g of "-methylbenzamide) -benzene are obtained. Melting | fusing point 99-100 degreeC

Elemental Analysis: C ₂₉ H ₃₅ N ₃ O ₃

Calculated Value (%): C 73.5 H 7.5 N 8.9

Found (%): C 73.3 H 7.6 N 8.9

Example 2

In the same manner as in Example 1, when 1- (3'-diethylaminopropoxy) -2,4-diaminobenzenetrichloride is condensed with 3-methylbenzoyl chloride and treated in the same manner below, 1- (3 '-Diethylaminopropoxy) -2,4-bis (3 "-methylbenzamide) -benzene is obtained. Melting point 113-114 degreeC 72% yield

Elemental Analysis Value: C ₂₉ H ₃₅ N ₃ O ₃

Calculated Value (%): C 73.5 H 7.5 N 8.9

Found (%): C 73.7 H 7.4 N 9.0

Example 3

To a mixture of 29 g of potassium carbonate, 110 ml of water and 110 ml of dioxane, 15 g of 1- [N- (2'-diethylaminoethyl) -carbamoyl] -2,4-diaminobenzenetrichloride was added and the mixture was placed in a nitrogen atmosphere. The solution which melt | dissolved 16.8 g of 2-methylbenzoyl chlorides in 20 ml of dioxanes was dripped over 1 hour, stirring at room temperature in the air. After stirring for 1.5 hours, the reaction mixture was extracted with benzene, and the basic material was collected from the organic layer with dilute hydrochloric acid in the water layer (if the hydrochloride is difficult to dissolve in water, the solution is dissolved with a small amount of methanol). After washing with water, the mixture was extracted with benzene again at pH 9-10 with potassium carbonate. The benzene layer is dried over potassium carbonate and concentrated, and the residue is purified by silica gel column chromatography (eluted with chloroform-methanol mixed solvent) and finally recrystallized from a benzene-ether mixed solvent to give 1- [N- (2 '-Diethylaminoethyl) -carbamoyl] -2,4-bis (2 "-methylbenzamido) -benzene is obtained. Melting | fusing point 157-158 degreeC.

Elemental Analysis Value: C ₂₉ H ₃₄ N ₄ O ₃

Calculated Value (%): C 71.6 H 7.0 N 11.5

Found (%): C 71.8 H 7.1 N 11.6

Example 4

In Example 1, dioxane was used instead of tetrahydrofuran, and the others were the same as in Example 1, except that 4- (3'-diethylaminopropoxy) -2,4-diaminobenzenetrichloride was 4- After condensation reaction with methylbenzoyl chloride, the reaction mixture is diluted with about 10 times of water, the precipitate is filtered off, and washed with ethanol after washing with water to give 1- (3'-diethylaminopropoxy) -2,4-bis-. (4 "-methylbenzamido) -Benzene is obtained. Melting | fusing point 148-149 degreeC. Yield 81%

Elemental Analysis Value: C ₂₉ H ₃₅ N ₃ O ₃

Calculated Value (%): C 73.5 H 7.5 N 8.9

Found (%): C 73.6 H 7.4 N 9.0

Example 5

10.4 g of 1- (3'-diethylaminopropoxy) -2,4-diaminobenzenetrichloride was added to a mixture of 6.2 g of potassium tinate, 19 g of sodium acetate trihydrate, 100 ml of water, and 100 ml of dioxane under ice-cooling. Immediately after, 13 g of benzoyl chloride was added, followed by stirring at room temperature for 2 hours. 500 ml of water was added to the mixture, and the mixture was adjusted to pH 9-10 using potassium carbonate. The precipitated crystals were filtered off, washed with water, and recrystallized twice with a mixed solvent of methanol and water to obtain 1- (3'-diethylaminopropoxy). 7.9 g of) -2,4-bis (benzamido) -benzene is obtained.

Melting Point 139 ~ 140 ℃

Elemental Analysis Value: C ₂ H ₃₁ N ₃ O ₃

Calculated Value (%): C 72.8 H 7.0 N 9.4

Found (%): C 72.5 H 7.1 N 9.5

Example 6

In the same manner as in Example 1, 1- (3'-dimethylaminopropoxy) -2,4-diaminobenzenetrihydrochloride is condensed with 2-methylbenzoyl chloride, and then treated in the same manner, and mixed with benzene-ether. Recrystallization with a solvent affords 1- (3'-dimethylaminopropoxy) -2,4-bis (2 "-methylbenzamido) -benzene.

Melting point 136-137 degreeC. Yield: 73%

Elemental Analysis Value: C ₂₇ H ₃₁ N ₃ O ₃

Calculated Value (%): C 72.8 H 7.0 N 9.4

Found (%): C 73.1 H 7.0 N 9.5

Example 7

Condensation reaction with 1- (3'-dimethylaminopropoxy) -2,4-diaminobenzene and 3-methylbenzoyl chloride in the same manner as in Example 6 results in 1- ( 3'-dimethylaminopropoxy) -2,4-bis (3 "-methylbenzamido) -benzene is obtained.

Melting point: 120-121 degreeC. Yield: 75%

Elemental Analysis Value: C ₂₇ H ₃₁ N ₃ O ₃

Calculated Value (%): C 72.8 H 7.0 N 9.4

Found (%): C 72.8 H 7.2 N 6.3

Example 8

In the same manner as in Example 6, condensation reaction of 1- (3'-dimethylaminopropoxy) -2,4-diaminobenzene with 4-methylbenzoyl chloride is carried out in the same manner below, and recrystallization from ethanol yields 1-. (3'-dimethylaminopropoxy) -2,4-bis- (4 "-methylbenzamido) -benzene is obtained.

Melting point: 163-164 degreeC. Yield: 68%

Elemental Analysis Value: C ₂₇ H ₃₁ N ₃ O ₃

Calculated Value (%): C 72.8 H 7.0 N 9.4

Found (%): C 72.5 H 7.1 N 9.5

Example 9

In the same manner as in Example 1, 1- (3'-diethylaminopropoxy) -2,4-diaminobenzene trihydrochloride was condensed with 2-methoxy-4-methylbenzoyl chloride to be treated in the same manner below. When recrystallized with methanol, 1- (3'-diethylaminopropoxy) -2,4-bis (2 "-methoxy-4" -methylbenzamido) -benzene is obtained.

Melting point: 127-129 degreeC. Yield: 65%

Elemental Analysis Value: C ₃₁ H ₃₉ N ₃ O ₅

Calculated Value (%): C 69.8 H 7.4 N 7.9

Found (%): C 69.7 H 7.6 N 8.1

Example 10

In the same manner as in Example 1, condensation reaction was carried out with 1- (3'-dimethylaminopropoxy) -2,4-diaminobenzenetrihydrochloride 2,3-dimethoxybenzoyl chloride, the reaction mixture was extracted with benzene, and an organic layer. After washing with water, the hydrochloric acid precipitated by inhalation of hydrogen chloride gas was precipitated, and this was dissolved in a methanol-water mixed solvent, added with aqueous potassium carbonate solution to give a free base, extracted with benzene, washed with benzene, dried and concentrated. do. Recrystallization of the residue with ethanol yields 1- (3'-dimethylaminopropoxy) -2,4-bis (2 ", 3" -dimethoxybenzamido) -benzene.

Melting point: 131-132 degreeC. Yield: 64%

Elemental Analysis Value: C ₂₉ H ₃₅ N ₃ O ₇

Calculated Value (%): C 64.8 H 6.6 N 7.8

Found (%): C 64.6 H 6.8 N 7.7

Example 11

In the same manner as in Example 1, condensation reaction of 1- (3'-diethylaminopropoxy) -2,4-diaminobenzenetrichloride with 2-chlorobenzoyl chloride was carried out, followed by extraction with benzene and the benzene layer. After washing with water and drying, the hydrochloric acid precipitated by inhalation of hydrogen chloride gas is filtered and recrystallized with ethanol. This is dissolved in water, brought to pH 9-10 using potassium carbonate, extracted again with benzene, washed with benzene layer and dried, concentrated, and the residue is recrystallized with a benzene-ether-hexane mixed solvent. -(3'-diethylaminopropoxy) -2,4-bis (2 "-chlorobenzamido) -benzene is obtained.

Melting point: 82-83 degreeC. Yield: 70%

Elemental Analysis Value: C ₂₇ H ₂₉ N ₃ O ₃ Cl ₂

Calculated Value (%): C 63.0 H 5.7 N 8.2

Found (%): C 63.1 H 5.9 N 8.1

Example 12

In Example 11, dioxane was used instead of tetrahydrofuran, and the others were the same, and 1- (3'-diethylaminopropoxy) -2,4-diaminobenzene trihydrochloride was 4-methoxybenzoyl chloride. After condensation reaction with water, diluted with water about 10 times after the reaction, the precipitated crystals were taken off, washed with water and recrystallized with ethanol to give 1- (3'-diethylaminopropoxy) -2,4-bis (4 " -Methoxybenzamido) -benzene is obtained.

Melting point: 149-150 degreeC. Yield: 80%

Elemental Analysis Value: C ₂₉ H ₃₅ N ₃ O ₅

Calculated Value (%): C 68.9 H 7.0 N 8.3

Found (%): C 68.8 H 7.0 N 8.3

Example 13

A mixture of 35 g of potassium carbonate, 50 ml of water, 150 ml of tetrahydrofuran and 11 g of 1- [N- (3'-diethylaminopropyl) -carbamoyl] -2,4-diaminobenzenetrichloride was heated and refluxed in a nitrogen atmosphere. While stirring under 35 g of 2-methylbenzoyl chloride was added dropwise thereto for 30 minutes, and reacted under the same conditions for 3 hours. In the same manner as in Example 3 below, 1- [N- (3′-diethylaminopropyl) -carbamoyl] -2,4-bis (2 ″ -methylbenzamido) -benzene is obtained.

Melting point: 138-140 degreeC. Yield: 65%

Elemental Analysis Value: C ₃₀ H ₃₆ N ₄ O ₃

Calculated Value (%): C 72.0 H 7.3 N 11.2

Found (%): C 71.9 H 7.2 N 11.5

Example 14

In the same manner as in Example 1, condensation reaction of 1- (4-dimethylaminobutoxy) -2,4-diaminobenzenetrichloride with 2-methylbenzoyl chloride was carried out in the same manner below to obtain a mixed solvent of benzene-ether. When recrystallized, 1- (4'-dimethylaminobutoxy) -2,4-bis (2-methylbenzamido) -benzene is obtained.

Melting point: 142-144 캜. Yield: 20%

Elemental Analysis Value: C ₂₈ H ₃₃ N ₃ O ₃

Calculated Value (%): C 73.2 H 7.2 N 9.1

Found (%): C 73.5 H 7.4 N 9.2

Example 15

In the same manner as in Example 14, condensation reaction of 1- (4'-dimethylaminobutoxy) -2,4-diaminobenzenetrichloride with 3-methylbenzoyl chloride is carried out in the same manner below. '-Dimethylaminobutoxy) -3,4-bis (3 "-methylbenzamido) -benzene is obtained.

Melting point: 105-107 degreeC. Yield: 79%

Elemental Analysis Value: C ₂₈ H ₃₃ N ₃ O ₃

Calculated Value (%): C 73.2 H 7.2 N 9.1

Found (%): C 73.1 H 7.3 N 9.2

Example 16

In the same manner as in Example 3, 1- [N- (2'-diethylaminoethyl) -carbamoyl] -2,4-diaminobenzene is condensed with 3-methylbenzoyl chloride and treated in the same manner below. In this case, 1- [N- (2'-diethylaminoethyl) -carbamoyl] -2,4-bis (3 "-methylbenzamido) -benzene is obtained. Melting point 167-168 degreeC yield 67%

Elemental Analysis Value: C ₂₉ H ₃₄ N ₄ O ₃

Calculated Value (%): C 71.6 H 7.0 N 11.5

Found (%): C 71.8 H 7.2 N 11.7

Example 17

In the same manner as in Example 6, when 1- [2 '-(N-morpholino) -ethoxy] -2,4-diaminobenzene is condensed with 2-methylbenzoyl chloride and treated in the same manner below, 1 -[2 '-(N-morpholino) -ethoxy] -2,4-bis (2 "-methylbenzamido) -benzene is obtained. Melting | fusing point 80-81 degreeC, yield 60%

Elemental Analysis Value: C ₂₈ H ₃₁ N ₃ O ₄

Calculated Value (%): C 71.0 H 6.6 N 8.6

Found (%): C 71.1 H 6.8 N 9.0

Example 18

In the same manner as in Example 13, when 1- [N- (3'-diethylaminopropyl) -carbamoyl] -2,4-diaminobenzene is condensed with 3-methylbenzoylcholide and treated in the same manner below , 1- [N- (3'-diethylaminopropyl) -carbamoyl] -2,4-bis (3 "-methylbenzamido) -benzene is obtained. Melting | fusing point 138-139 degreeC yield 66%

Elemental Analysis Value: C ₃₀ H ₃₆ N ₄ O ₃

Calculated Value (%): C 72.0 H 7.3 N 11.2

Found (%): C 71.8 H 7.2 N 11.3

Example 19

In the same manner as in Example 3, 1- [N-2′-diethylaminoethyl) -carbamoyl] -2,4-diaminobenzenetrichloride is condensed with 4-methylbenzoyl chloride and treated in the same manner below. 1- [N- (2'-diethylaminoethyl) -carbamoyl] -2,4-bis (4 "-methylbenzamido) -benzene is obtained. Melting | fusing point 178-179 degreeC. Yield 64 %

Elemental Analysis Value: C ₂₉ H ₃₄ N ₄ O ₃

Calculated Value (%): C 71.6 H 7.0 N 11.5

Found (%): C 71.5 H 7.2 N 11.6

Example 20

In the same manner as in Example 1, 4-condensation reaction of 4-methoxybenzoyl chloride was carried out with 1- (3'-dimethylaminopropoxy) -2,4-diaminobenzenetrichloride, extracted with benzene after the reaction, and the benzene layer was After washing with water, it is dried over potassium carbonate and decolorized with silica gel. Hydrogen chloride gas is sucked into this benzene solution, the precipitated hydrochloride is filtered off, washed with an ethanol-acetone mixed solvent, dissolved in a methanol-water mixed solvent, an aqueous potassium carbonate solution is added to the free base, and extracted with benzene. The benzene layer was washed with water, dried and concentrated, and the residue was recrystallized with ethanol to give 1- (3'-dimethylaminopropoxy) -2,4-bis (4 "-methoxybenzamido) -benzene. Lose.

Melting point 171-172 캜. Yield 62%

Elemental Analysis Value: C ₂₇ H ₃₁ N ₃ O ₅

Calculated Value (%): C 67.9 H 6.5 N 8.8

Found (%): C 68.0 H 6.6 N 8.6

Example 21

17 g of potassium carbonate was dissolved in 40 ml of water, 90 ml of dioxane was added, and 6.6 g of 1- (2'-diethylaminoethoxy) -2,4-diaminobenzene trihydrochloride and 2- 1.1 g of ethoxybenzoyl chloride is added and the mixture is stirred at room temperature for 1 hour. 500 ml of water is then added, insoluble matters are separated, washed with water, dissolved in acetone, hydrogen chloride gas is inhaled into the solution, ether is added to precipitate hydrochloride, and this is separated and recrystallized from ethanol. 6.8 g of ethylaminoethoxy) -2,4-bis (2 "-ethoxybenzamido) benzene hydrochloride are obtained. Melting point 194-195 degreeC

Elemental Analysis Value: C ₃₀ H ₃₈ N ₃ O ₅ Cl

Calculated Value (%): C 64.8 H 6.9 N 7.6

Found (%): C 64.7 H 6.9 N 7.7

Example 22

4.2 g of potassium carbonate and 13 g of sodium acetate trihydrate were dissolved in 80 ml of water, 80 ml of dioxane was added, and 1- (2'-diethylaminoethoxy) -2,4-diaminobenzene was added to the mixture at 5 to 10 ° C. Immediately after adding 6.6 g of trichloride, 12 g of 2-acetoxybenzoyl chloride was added, followed by stirring at 5 to 10 ° C for 1 hour. Then, the mixture is returned to room temperature, 30 ml of concentrated ammonia water is added, the mixture is left at room temperature for 30 minutes, 500 ml of water is added to pH 8 with dilute hydrochloric acid, and precipitated crystals are filtered out. This is washed with water and then dried by dissolving hydrogen chloride gas in saturated methanol, and concentrated to dryness, and the residue is recrystallized from ethanol to give 1- (2'-diethylaminoethoxy) -2,4-bis (2 "-hydroxy). Benzamido) -benzene hydrochloride 5.9g is obtained Melting point 216-217 degreeC

Elemental Analysis Value: C ₂₆ H ₃₀ N ₃ O ₅ Cl

Calculated Value (%): C 62.5 H 6.0 N 8.4

Found (%): C 62.4 H 6.1 N 8.3

Example 23

Immediately after adding 3.5 g of N- (2,4-diaminophenyl) -N'-methylpiperazine Trichloride at 5-10 ° C to a mixture of 2.8 g of potassium carbonate, 2.5 g of sodium carbonate, 30 ml of water and 40 ml of dioxane, 6 g of acetoxybenzoyl chloride is added and stirred at 5 to 10 ° C. for 1 hour. Subsequently, 20 ml of concentrated ammonia water is added to the mixture, which is allowed to stand at room temperature for 30 minutes, and then 300 ml of water is added, the pH is adjusted to 8 with dilute hydrochloric acid, and the precipitated crystals are filtered out. After washing with water and drying the hydrogen chloride gas in saturated methanol, it is concentrated under reduced pressure, and the residue is recrystallized with a methanol-water mixed solvent to give N- [2,4-bis (2'-hydroxybenzamido)-. 2.9 g of phenyl] -N'-methyl piperazine hydrochlorides are obtained. Melting Point 290 ~ 294 ℃ (Decomposition)

Elemental Analysis Value: C ₂₅ H ₂₇ N ₄ O ₄ Cl

Calculated Value (%): C 62.2 H 5.6 N 11.6

Found (%): C 62.2 H 5.7 N 11.7

Example 24

73 g of 2-methoxybenzoyl chloride with stirring in a nitrogen atmosphere to a mixture of 120 g of potassium carbonate, 300 ml of water, 600 ml of dioxane and 47.2 g of 1- (3'-diethylaminopropoxy) -2,4-diamino benzene phosphate Was added dropwise at 5 to 10 ° C., stirred at 5 to 10 ° C. for 30 minutes, then stirred at room temperature for 2 hours, and then 3 liters of water was added to extract with benzene. The organic layer was washed with water, dried and concentrated, and the residue was recrystallized with a methanol / water mixed solvent and recrystallized with a benzene-hexane mixed solvent to give 1- (3'-diethylaminopropoxy) -2,4-bis (2 "- Dimethoxybenzamido) -46g of benzene is obtained Melting point 714-115 degreeC

Elemental Analysis Value: C ₂₉ H ₃₅ N ₃ O ₅

Calculated Value (%): C 68.9 H 7.0 N 8.3

Found (%): C 69.3 H 7.1 N 8.4

Example 25

Immediately after adding 19 g of N- (2,4-diaminophenyl) -N'-methylpiperazine trichloride at 5 to 10 ° C. to a mixture of 12.4 g of potassium carbonate, 37 g of sodium phosphate trihydrate, 240 ml of water and 240 ml of dioxane, 31 g of 2-methoxybenzoyl chloride is added, and it stirred for 30 minutes at 5-10 degreeC, and then 30 minutes at room temperature. To the mixture, 1 liter of water was added, and 30 g of potassium carbonate was added and left overnight. The precipitated crystals were filtered off, washed with water and dried and recrystallized with ethyl acetate. N- [2,4-bis (2'-methoxybenzamido) 20 g of) -phenyl] -N'-methylpiperazines are obtained. Melting Point 177 ~ 178 ℃

Elemental Analysis Value: C ₂₇ H ₃₀ N ₄ O ₄

Calculated Value (%): C 68.3 H 6.4 N 11.8

Found (%): C 68.2 H 6.4 N 11.9

Example 26

Condensation reaction with 1- (2'-diethylaminoethoxy) -2,4-diaminobenzenetrihydrochloride 2-methoxybenzoyl chloride in the same manner as in Example 21 and the product was recrystallized in the state of an organic base. -(2'-diethylaminoethoxy) -2,4-bis (2 "-methoxybenzamido) -benzene is obtained. Melting | fusing point 143-144 degreeC. Yield 69%

Elemental Analysis Value: C ₂₈ H ₃₃ N ₃ O ₅

Calculated Value (%): C 68.4 H 6.8 N 8.6

Found (%): C 68.7 H 6.9 N 8.5

Example 27

In the same manner as in Example 21, 1- (2'-dimethylaminoethoxy) -2,4-diaminobenzenetrichloride was condensed with 2-methoxybenzoyl chloride, and after the reaction, the product was extracted with benzene to give an organic layer. The basic material is collected in the water layer with dilute hydrochloric acid from (if hydrochloride is difficult to dissolve in water, it can be dissolved using a small amount of methanol). The water layer was washed with benzene, added with potassium carbonate to pH 9-10, and extracted again with benzene. The extract was washed with water, dried over potassium carbonate, concentrated, and the residue was purified by silica gel column chromatography (eluted with a mixed solvent of benzene-methanol) and recrystallized with methanol to give 1- (2'-dimethylaminoethoxy). -2,4-bis (2 "-methoxybenzamido) -benzene is obtained. Melting | fusing point 149-150 degreeC yield 62%

Elemental Analysis Value: C ₂₆ H ₂₉ N ₃ O ₅

Calculated Value (%): C 67.4 H 6.3 N 9.1

Found (%): C 67.3 H 6.3 N 9.1

Example 28

To a mixture of 5 g of potassium carbonate, 30 ml of water, and 30 ml of dioxane, 3.9 g of 1- (2'-diethylaminoethyl) -2,4-diaminobenzenetrichloride and 5.4 g of 2-ethoxybenzoyl chloride at 5 to 10 ° C Was added and stirred at 5 to 10 ° C. for 1 hour. Subsequently, 200 ml of water is added to the mixture, the mixture is extracted with benzene at a pH of 9 to 10, and the extract is washed with water, dried with hydrogen chloride gas to precipitate hydrochloride, which is recrystallized from isopropyl alcohol. The crystals are dissolved in water, potassium carbonate is added, extraction is performed with benzene, the extract is concentrated to dryness, and the residue is recrystallized from a tetrahydrofuran ether ether hexane mixed solvent to obtain 1- (2'-diethylamino). 4.0 g of ethyl) -2,4-bis (2 "-ethoxybenzamido) -benzene are obtained. Melting | fusing point 91-92 degreeC

Elemental Analysis Value: C ₃₀ H ₃₇ N ₃ O ₄

Calculated Value (%): C 71.5 H 7.4 N 8.3

Found (%): C 71.7 H 7.5 N 8.1

Example 29

To a mixture of 3.5 g of potassium carbonate, 11 g of sodium carbonate trihydrate, 50 ml of water, and 60 ml of tetrahydrofuran, 5 g of 1- (2'-dimethylaminoethyl) -2,4-diaminobenzenetrichloride at 0-5 ° C. and 2-acetate 11 g of oxybenzoyl chlorides are added and stirred at 5 to 10 ° C for 1 hour. 40 ml of concentrated ammonia water was added to the reaction mixture, which was allowed to stand at room temperature for 30 minutes. Then, 500 ml of water was added, pH 7-8 was diluted with dilute hydrochloric acid. The insolubles were separated, washed with water, and dissolved in benzene. Precipitated and recrystallized with isopropyl alcohol to obtain 4.8 g of 1- (2'-dimethylaminoethyl) -2,4-bis (2 "-hydroxybenzamido) -benzene hydrochloride. Melting point 245-247 ℃ (decomposition)

Elemental Analysis Value: C ₂₄ H ₂₆ N ₃ O ₄ Cl

Calculated Value (%): C 63.2 H 5.7 N 9.2

Found (%): C 63.2 H 5.7 N 8.9

Example 30

To a mixture of 22 g of potassium carbonate, 80 ml of water, and 90 ml of dioxane, 11 g of 1- [N- (2'-diethylaminoethyl) -carbamoyl] -2,4-diaminobenzene trichloride was added at 5 to 10 ° C. In addition, 11.2 g of 2-hatoxybenzoyl chlorides are dripped over 30 minutes in nitrogen atmosphere, and it stirred at room temperature for 1 hour. 500 ml of water was added to the reaction mixture, followed by extraction with benzene. The extract was washed with water, dried with hydrogen chloride gas to precipitate hydrochloride, which was recrystallized with ethanol to give 1- [N- (2'-diethylaminoethyl) -ka. Abamoyl] -2,4-bis (2 "-methoxybenzamido) -benzene hydrochloride 11g is obtained. Melting | fusing point 181-182 degreeC

Elemental Analysis Value: C ₂₉ H ₃₅ N ₄ O ₅ Cl

Calculated Value (%): C 62.7 H 6.4 N 10.1

Found (%): C 62.5 H 6.4 N 10.0

Example 31

In the same manner as in Example 30, 1- [N- (2'-diethylaminoethyl) -carbamoyl] -3,5-diaminobenzenetrichloride was condensed with 2-methoxybenzoyl chloride, and the same procedure was followed. After hydrolysis, the resulting hydrochloride is recrystallized from isopropyl alcohol to give 1- [N- (2'-diethylaminoethyl) -carbamoyl] -3,5-bis (2 "-methoxybenzamido). -Benzene hydrochloride is obtained Melting point 187-189 degreeC 72% yield

Elemental Analysis Value: C ₂₉ H ₃₅ N ₄ O ₅ Cl

Calculated Value (%): C 62.7 H 6.4 N 10.1

Found (%): C 62.9 H 6.3 N 10.0

Example 32

In the same manner as in Example 29, when 1- (2'-diethylaminoethyl) -2,4-diaminobenzenetrichloride is condensed with 2-acetoxybenzoyl chloride and treated in the same manner below, 1- (2 '-Diethylaminoethyl) -2,4-bis (2 "-hydroxybenzamido) -benzene hydrochloride is obtained. Melting point 246-248 degreeC (decomposition), yield 49%

Elemental Analysis Value: C ₂₆ H ₃₀ N ₃ O ₄ Cl

Calculated Value (%): C 64.5 H 6.2 N 8.7

Found (%): C 64.3 H 6.0 N 8.9

Example 33

3 g of free base of crude 1- (2'-diethylaminoethoxy) -2,4-bis (2 "-hydroxybenzamido) -benzene obtained in Example 22 was dissolved in 20 ml of acetic anhydride, and overnight After leaving to stand, hydrogen chloride gas is sucked in to form hydrochloride, which is concentrated under reduced pressure, and the residue is recrystallized from acetone to give 1- (2'-diethylaminoethoxy) -2,4-bis (2 "-ace Oxybenzamido) -2.1 g of benzene hydrochloride is obtained. Melting Point 168 ~ 170 ℃

Elemental Analysis Value: C ₃₀ H ₃₄ N ₃ O ₇ Cl

Calculated Value (%): C 61.7 H 5.9 N 7.2

Found (%): C 61.8 H 6.2 N 7.0

Example 34

1 g of the free base of the prepared N- [2,4-bis (2'-hydroxybenzamido) -phenyl] -N'-methylpiperazine obtained in Example 23 was treated in the same manner as in Example 33. Recrystallization with isopropyl alcohol yields 0.5 g of N- [2,4-bis (2'-acetoxybenzamido) -phenyl] -N'-methylpiperazine hydrochloride. Melting Point 228-230 ° C (Decomposition)

Elemental Analysis Value: C ₂₉ H ₃₁ N ₄ O ₆ Cl

Calculated Value (%): C 61.4 H 5.5 N 9.9

Found (%): C 61.0 H 5.5 N 9.7

Example 35

In the same manner as in Example 21, condensation reaction of 1- (2'-diethylaminoethyl) -2,4-diaminobenzenetrichloride with 2-methoxybenzoyl chloride was completed. After completion of the reaction, the mixture was extracted with benzene and the extract was extracted. After washing with water, inhalation of hydrogen chloride gas precipitates hydrochloride, which is filtered off and recrystallized from isopropyl alcohol to yield 1- (2'-diethylaminoethyl) -2,4-bis (2 "-methoxybenzamido)-. Benzene hydrochloride is obtained, yield 64%, melting | fusing point 188-189 degreeC.

Elemental Analysis Value: C ₂₈ H ₃₄ N ₃ O ₄ Cl

Calculated Value (%): C 65.7 H 6.7 N 8.2

Found (%): C 65.4 H 6.7 N 8.0

Example 36

In the same manner as in Example 30, 1- [N- (3'-diethylaminopropyl) -carbamoyl] -2,4-diaminobenzenetrichloride was condensed with 2-methoxybenzoyl chloride, and the same procedure was followed. After treatment, the resulting hydrochloric acid is recrystallized from isopropyl alcohol. Subsequently, when recrystallized with a benzene-ether mixed solvent again with a free base, 1- [N- (3'-diethylaminopropyl) -carbamoyl] -2,4-bis (2 "-methoxybenzamido ) -Benzene is obtained Melting point 107-108 ° C Yield 97%

Elemental Analysis Value: C ₃₀ H ₃₆ N ₄ O ₅

Calculated Value (%): C 67.6 H 6.8 N 10.5

Found (%): C 67.8 H 6.8 N 10.5

Example 37

In the same manner as in Example 27, condensation reaction of 1- (3'-dimethylaminopropoxy) -2,4-diaminobenzenetrichloride with 2-methoxybenzoyl chloride was carried out in the same manner below to obtain hydrochloride, Recrystallization with isopropyl alcohol yields 1- (3'-dimethylaminopropoxy) -2,4-bis (2 "-methoxybenzamido) -benzene hydrochloride. Melting point 180-181 degreeC, yield 68%

Elemental Analysis Value: C ₂₇ H ₃₂ N ₃ O ₅ Cl

Calculated Value (%): C 63.1 H 6.3 N 8.2

Found (%): C 62.9 H 6.3 N 8.3

Example 38

In the same manner as in Example 27, condensation reaction was carried out with 1- (2'-dimethylamino-2 ', 2'-dimethylethoxy) -2,4-diaminobenzenetrichloride 2-methoxybenzoyl chloride to liberate the product. Purified by silica gel column chromatography as it was (as eluted with CHCl ₃ : methanol = 10: 1) as it was, and then 1- (2'-dimethylamino-2 ', 2'-dimethylethoxy) -2,4-bis (2 "-Methoxybenzamido) -benzene is obtained as a colorless amorphous powder. Yield 52%

Elemental Analysis Value: C ₂₈ H ₃₃ N ₃ O ₅

Calculated Value (%): C 68.4 H 6.8 N 8.6

Found (%): C 68.3 H 7.1 N 8.5

IR (KBr Dish) (cm ^-1 ): 3,330, 2,900, 1,660, 1,590, 1,540, 1,480, 1,300, 1,020, 750

NMR (CDCl ₃ solution δ): 3.98 (6H, s), 3.87 (2H, s), 2.20 (6H, s), 1.12 (6H, s)

Example 39

In the same manner as in Example 27, the condensation reaction of 2,4-diamino-N-methyl-N- (2'-methylaminoethyl) -aniline trichloride with 2-methoxy benzoyl chloride was carried out, and the product was left in the free base state. Purification by silica gel column chromatography (elution with CHCl ₃ : methanol = 10: 1) yields 2,4-bis (2'-methoxybenzamido) -N-methyl-N- (2 "-dimethylaminoethyl) -Aniline is obtained as a colorless amorphous powder, yield 51%

Elemental Analysis Value: C ₂₇ H ₃₂ N ₄ O ₄

Calculated Value (%): C 68.0 H 6.8 N 11.8

Found (%): C 68.0 H 6.9 N 11.5

IR (KBr Dish) (cm ^-1 ): 3,340, 3,270, 2,900, 1,660, 1,540, 1,470, 1,290, 1,020, 750

NMR (CDCl ₃ solution δ): 3.98 (6H, s), 3.09 (2H, t, J 9Hz), 2.69 (3H, s), 2.30 (H, t, J 9Hz), 2.07 (6H, s)

Example 40

In the same manner as in Example 35, when 1- [2 '-(N-morpholino) -ethyl] -2,4-diaminobenzene trichloride is condensed with 2-methoxybenzoyl chloride and treated in the same manner below 1- [2 '-(N-morpholino-ethyl] -2,4-bis (2 "-methoxybenzamido) -benzene hydrochloride is obtained. Melting | fusing point 220-221 degreeC, yield 59%

Elemental Analysis Value: C ₂₈ H ₃₂ N ₃ O ₅ Cl

Calculated Value (%): C 63.9 H 6.1 N 8.0

Found (%): C 63.7 H 6.0 N 7.9

Example 41

In the same manner as in Example 35, 1- [2 '-(-N-piperidino) -ethyl] -2,4-diaminobenzenetrichloride was condensed with 2-methoxybenzoyl chloride and treated in the same manner below. The hydrochloric acid produced is then separated and recrystallized from isopropyl alcohol. Subsequently, when recrystallized with a benzene-ether mixed solvent again using a free base, 1- [2 '-(N-piperidino-ethyl] -2,4-bis (2 "-methoxybenzamido) -benzene is obtained. Obtained.

Elemental Analysis Value: C ₂₉ H ₃₃ N ₃ O ₄

Calculated Value (%): C 71.4 H 6.8 N 8.6

Found (%): C 71.3 H 6.9 N 8.8

Example 42

In the same manner as in Example 30, 1- [N- (2'-diethylaminoethyl) -carmoyl] -2,5 diaminobenzene trichloride is condensed with 2-methoxybenzoyl chloride and treated in the same manner below. A lower surface of 1- [N- (2'-diethylaminoethyl) -carbamoyl] -2,5-bis (2 "-methoxybenzamido) -benzene hydrochloride is obtained. Melting | fusing point 213-214 degreeC (decomposition | disassembly) ), Yield 67%

Elemental Analysis Value: C ₂₉ H ₃₅ N ₄ O ₅ Cl

Calculated Value (%): C 62.7 H 6.4 N 10.1

Found (%): C 62.6 H 6.2 N 9.8

Example 43

In the same manner as in Example 13, when 1- [N- (3'-dimethylaminopropyl) -carbamoyl] -2,4-diaminobenzene is condensed with 2-methylbenzoyl chloride and treated in the same manner below, 1- [N- (3'-dimethylaminopropyl) -carbamoyl] -2,4-bis (2 "-methylbenzamido) -benzene is obtained. Melting point 164-165 degreeC yield 68%

Elemental Analysis Value: C ₂₈ H ₃₂ N ₃ O ₄

Calculated Value (%): C 71.2 H 6.8 N 11.9

Found (%): C 70.9 H 6.9 N 11.7

Example 44

In the same manner as in Example 13, when 1- [N- (3'-dimethylaminopropyl) -carbamoyl] -2,4-diaminobenzene is condensed with 4-methylbenzoyl chloride and treated in the same manner below, 1- [N- (3'-dimethylaminopropyl) -carbamoyl] -2,4-bis (4 "-methylbenzamido) -benzene is obtained. Melting | fusing point 195-196 degreeC yield 63%

Elemental Analysis Value: C ₂₈ H ₃₂ N ₃ O ₄

Calculated Value (%): C 71.2 H 6.8 N 11.9

Found (%): C 71.1 H 6.7 N 11.9

Example 45

In the same manner as in Example 13, when 1- [N- (3'-dimethylaminopropyl) -carbamoyl] -2,4-diaminobenzene is condensed with 3-methylbenzoyl chloride and treated in the same manner below, 1- [N- (3'-dimethylaminopropyl) -carbamoyl] -2,4-bis (3 "-methylbenzamido) -benzene is obtained. Melting point 172-173 degreeC. Yield 71%

Elemental Analysis Value: C ₂₈ H ₃₂ N ₃ O ₄

Calculated Value (%): C 71.2 H 6.8 N 11.9

Found (%): C 71.3 H 6.7 N 11.7

Example 46

In the same manner as in Example 13, 1- [N- (3'-dimethylaminopropyl) -carbamoyl] -2,4-diaminobenzene was condensed with 2-methoxy-4-methylbenzoyl chloride, and In the same manner, 1- [N- (3'-dimethylaminopropyl) -carbamoyl] -2,4-bis (2 "-methoxy-4" -methylbenzamido) -benzene is obtained. Melting point 127-129 degreeC. Yield 60%

Elemental Analysis Value: C ₃₀ H ₃₆ N ₄ O ₅

Calculated Value (%): C 67.7 H 6.8 N 10.5

Found (%): C 67.5 H 6.9 N 10.4

Example 47

In the same manner as in Example 13, when 1- [N- (3'-dimethylaminopropyl) -carbamoyl] -2,4-diaminobenzene is condensed with benzoyl chloride and treated in the same manner below, 1- [ N- (3'-dimethylaminopropyl) -carbamoyl] -2,4-bis (benzamido) -benzene is obtained. Melting point 196-197 degreeC. Yield 66%

Elemental Analysis Value: C ₂₆ H ₂₈ N ₄ O ₃

Calculated Value (%): C 70.3 H 6.4 N 12.6

Found (%): C 70.2 H 6.4 N 12.5

Claims (1)

Bis- (benzamido) of the following general formula (I) characterized by reacting a compound of the following general formula (II) with a compound of the following general formula (III) or a derivative in which the carboxyl group thereof is functional (functional) -Process for producing benzene oil.

In each formula above, X is a direct bond or oxygen, -CONH- or

ego, R ₁ is a linear or branched lower alkylene group, R ₂ and R ₃ are each a lower alkyl group which may be the same or different, and other R ₂ and R ₃ may be bonded via a direct bond or a heteroatom, R ₄ is a lower alkyl group, other R ₄ may be combined with R ₂ or R ₃ , Y and Z are the same or different hydrogen atoms, lower alkyl groups, hydroxyl groups, lower alkoxy groups, lower alkanoyl groups or halogen atoms.