KR790001741B1 - Process for the praparation of bezoic amides - Google Patents

Abstract

Benzamide (I; X,Y =same or different, H loweralkyl, or iower ; R1, R2 = same or diff- erent lower alkyk, R1, R2 are bonded directly or together with hetero atom; A =lower alkylene gro-up), which have antiuicer astivity, were preqd. by reaction of coepd. (II) with compd. (III)

Description

Preparation of Benzoic Acid Amides

The present invention is a general formula

Wherein X and Y are the same or different and mean a hydrogen atom, a lower alkyl group or a lower alkoxy group. A is a lower alkylene group, R ₁ , R ₂ means the same or different lower alkyl group, and R ₁ and R ₂ may be bonded directly or via a heteroatom).

According to the present invention, the compound of general formula (I) is

(Where X and Y have the meaning of electricity) and the compound represented by general formula

It is obtained by reacting the compound represented by (wherein A, R ₁ and R ₂ have the meaning of electricity).

The compound of formula (I) obtained by the present invention is a novel compound and is useful as a medicine because it has an excellent preventive and therapeutic effect against various experimental ulcers in experimental animals.

The compound of the formula (II) used in the present invention is obtained by condensing a 2,4-diaminobenzoic acid with a reactive derivative in a benzoic acid having a substituent X or Y or a carboxyl group thereof.

In carrying out the present invention, it is preferable to use condensation aids such as phosphorus oxychloride, phosphorus trichloride, silicon tetrachloride, phosphate esters, thionyl chloride, phosphorus pentachloride, dicyclohexyl carbodiimide, and the like Depending on the type of condensation aid, tetrahydrofuran, dioxane, acetonitrile, benzene, xylene, pyridine, dimethylformamide, triethylamine and the like are suitably selected and used. It is preferable to perform reaction temperature at room temperature to the reflux temperature of a solvent.

Further, when the compound of formula (III) is reacted with an excess of the compound of formula (II) in an amount of 1: 1 to 1: 7, preferably 1: 1.2 to 1: 2, a preferable result is obtained. Lose. Isolation of the target product is carried out in accordance with the phases and, if necessary, purified by column chromatography, recrystallization or the like.

The target substance of this invention obtained in this way can be made into acid addition salt by a conventional method as needed.

Example 1

6.9 g of 2-diethylaminoethylamine are dissolved in 30 ml of pyridine, 2,7 g of phosphorus trichloride is added dropwise thereto (5 minutes) while stirring, and the mixture is stirred at room temperature for 40 minutes. To this mixture, 4.2 g of 2,4-bis (2'-methoxybenzamido) -benzoic acid is added and heated to reflux for 4 hours. After distilling off the solvent at reduced pressure, water is added to the residue, followed by extraction with benzene. Dilute hydrochloric acid is added to the extract, and the basic substance is taken into the water layer (if the hydrochloride is difficult to dissolve in water, it is dissolved using a small amount of methanol). The water layer is washed with ether, and then the potassium carbonate is pH 9-10. Extract with benzene. The benzene layer was washed with water, concentrated and concentrated, and the residue was purified by silica gel column chromatography (soluble with chloroform-methanol), dissolved in benzene again, and extracted with hydrogen chloride gas. The precipitate was recrystallized with ethanol to give 1-. [N- (2'-diethylaminoethyl) -carbamoyl] -2,4-bis (2 "-methoxybenzamido) -benzene hydrochloride 3.5g was obtained. Melting | fusing point 181-182 degreeC.

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

Theoretic value (%): C 62.7 H 6.4 N 10.1

Found (%): 62.8 6.3 10.0

Example 2

4.7 g of 3-diethylamino-1-propylamine was dissolved in 30 ml of pyridine, 1.5 g of phosphorus oxychloride was added thereto while stirring with water, followed by stirring at room temperature for 30 minutes, followed by 2,4-bis (2'-methoxy Benamido)-3.9 g of benzoic acid is added and heated to reflux for 4 hours. The treatment was carried out in the same manner as in Example 1, and recrystallized from a mixed solvent of benzene-ether in a free base state, followed by 1- [N- (3'-diethylaminopropyl) -carmoyl] -2,4-bis (2 "- Methoxybenzamido) -benzene was obtained by 3.0 g, Melting point 107-108 degreeC.

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

Theoretic value (%): C 67.6 H 6.8 N 10.5

Found (%): 67.8 6.9 10.4

Example 3

In the same manner as in Example 1, crystals are condensed with 3-dimethylamino-1-propylamine and 2,4-bis (2'-dimethylbenzamido) -benzoic acid, and after completion of the reaction, water is added to the reaction solution to precipitate. Was filtered, washed with water and recrystallized with ethyl acetate to obtain 1- [N- (3'-dimethylaminopropyl) -carbamoyl] -2,4-bis (2 "-methylbenzamido) -benzene. Yield 63%, Melting | fusing point 164-165 degreeC.

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

Theoretic value (%): C 71.2 H 6.8 N 11.9

Found (%): 71.0 6.9 11.8

Example 4

After stirring a mixture of 2,4-bis (3'-methylbenzamido) -benzoic acid, 3.9 g, 30 ml of tetrahydrofuran, and 2.3 g of dicyclohexylcaraboimide at 10C for 10 minutes, 3-diethylamino- 2.0 g of 1-propylamine are added, and it refluxed for 2 hours. After allowing to cool, the reaction solution was filtered, and the insolubles were washed with 20 ml of tetrahydrofuran. The filtrate and the washings were combined, 100 ml of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated, and the residue was purified by silica gel column chromatography (eluted with chloroform-methanol mixed solvent), and then recrystallized with benzene ether mixed solvent to give 1- [N- (3'-diethylamino). Propyl) -carbamoyl] -2,4-bis (3 "-methylbenzamido) -benzene 3.1g was obtained. Melting | fusing point 138-139 degreeC.

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

Theoretic value (%): C 72.0 H 7.3 N 11.2

Found (%): 71.9 7.5 11.2

Example 5

The treatment was carried out in the same manner as in Example 2 using 2-diethylaminoethylamine and 2,4-bis (2'-methylbenzamido) -benzoic acid to give 1- [N- (2'-diethylaminoethyl ) -Carbamoyl] -2,4-bis (2 "-methylbenzamido) -benzene was obtained. The yield 61%, melting | fusing point 157-158 degreeC.

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

Theoretic value (%): C 71.6 H 7.0 N 11.5

Found (%): 71.8 7.2 11.6

Example 6

3.9 g of 2,4-bis (2'-methylbenzamido) -benzoic acid is dissolved in 20 ml of pyridine, 1.3 g of thioyl chloride is added thereto, stirred, and 5 minutes later, 3-dimethylamino-1-propylamine 4 g is added and it heats at 70-80 degreeC for 1 hour. After cooling, 40 ml of water is added, and the precipitated crystals are filtered off, washed with water, and recrystallized with ethyl acetate to give 1-N- (3'-dimethylaminopropyl) -carbamoyl] -2,4-bis (2 "-methyl Benzamido)-benzene was obtained 3.7g, melting | fusing point 164-165 degreeC.

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

Theoretic value (%): C 71.2 H 6.8 N 11.9

Found (%): 71.1 6.9 11.7

Example 7

Treatment was carried out in the same manner as in Example 6 using 2,4-bis (benzamido) -benzoic acid 3-dimethylamino-1-propylamine and 1- [N- (3'-dimethylaminopropyl) -carbamoyl ] -2,4-bis (benzamido) -benzene was obtained. Yield 68%, Melting | fusing point 196-197 degreeC.

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

Theoretic value (%): C 70.3 H 6.4 N 12.6

Found (%): 70.1 6.5 12.5

Example 8

In the same manner as in Example 1, 3-dimethylamino-1-propylamine and 2,4-bis (4'-methylbenzamido) -benzoic acid are condensed, allowed to cool after reaction, and crystallized by adding water to precipitate. The mixture was washed with water, dried and recrystallized with a chloroform-ether mixed solvent to give 1- [N- (3'-dimethylaminopropyl) -carbamoyl] -2,4-bis (4 "-methylbenzamido) -benzene. Yield 53%, melting | fusing point 195-196 degreeC.

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

Theoretic value (%): C 71.2 H 6.8 N 11.9

Found (%): 71.1 6.9 11.8

Example 9

The treatment was carried out in the same manner as in Example 4 using 2,4-bis (2'-methoxy-4'-methylbenzamido) -benzoic acid and 3-dimethylamino-1-propylamine, and recrystallized with benzene to obtain 1 -[N- (3'-dimethylaminopropyl) -carbamoyl] -2,4-bis (2 "-methoxy-4" -methylbenzamido) -benzene was obtained. Yield 59%, Melting | fusing point 127-129 degreeC.

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

Theoretic value (%): C 67.7 H 6.8 N 10.5

Found (%): 67.7 6.8 10.4

Example 10

In the same manner as in Example 1, 3-dimethylamino-1-propylamine and 2,4-bis (3'-methylbenzamido) -benzoic acid are condensed, and crystals are precipitated by adding water to the reaction solution after the reaction. After filtration and washing with water, chloroform-ether recrystallization was carried out to obtain 1- [N- (3'-dimethylaminopropyl) -carbamoyl] -2,4-bis (3 "-methylbenzamido) -benzene. Yield 61%, Melting | fusing point 172-173 degreeC.

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

Theoretic value (%): C 71.2 H 6.8 N 11.9

Found (%): 71.4 6.7 11.7

Claims (1)

General formula

Wherein X and Y are the same or different and represent a hydrogen atom, a lower alkyl group or a lower alkoxy group.

Reacted with a compound represented by (wherein A is a lower alkylene group, R ₁ and R ₂ are the same or different lower alkyl groups, and R ₁ and R ₂ may be bonded directly or through a heteroatom). General formula characterized by

A process for producing benzoic acid amides represented by (wherein X, Y, A, R ₁ and R ₂ have the meaning of electricity).