KR790001742B1 - Process for the preparation of benz anllide derivatives - Google Patents

Abstract

Benzanilides (I; X,Y is same or not hydrogen, lower alkyl, lower alkoxy, A = lower alkylene, R1,R2 is same or not, lower alkyl), effection on peptic ulcer and having vasodilating activity were prepd. by reaction of MHR1R2 and II. Thus, 4.7g II in dioxane and 40% aq.dimethylamine were heated at 90-100≰C to give 3.1g I.

Description

Preparation of Benzanilide Derivatives

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 means a lower alkylene group and R ₁ , R ₂ are the same or different and are lower alkyl groups, in which case R ₁ and R ₂ may be bonded directly or through a heteroatom)

It relates to a manufacturing method of benzanilide derivative represented by.

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

(Where X, Y and A mean electricity and Hal means halogen atom)

Compound represented by general formula

It is obtained by reacting the compound represented by (wherein, 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 has a prophylactic and therapeutic effect against various experimental gastric ulcers and a peripheral blood circulation enhancing effect in laboratory animals, and thus is useful as a medicine.

The compound of formula (II) used in the present invention is, for example, condensation of 2,4- (bis (benzamido) -phenol having a substituent X, Y with α, ω-dihaloankan or 4- (ω-haloalkoxy)-It is obtained by methods, such as condensation of benzoyl chloride which has a metaphenylenediamine and substituent X, Y.

In carrying out the present invention, the compound of formula (II) is usually reacted at 20 to 150 ° C, preferably at 30 to 100 ° C. At this time, for example, water, methanol, ethanol, butanol, benzene, gluten, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide and the like and mixtures thereof are used as the solvent. The solvent may also be combined using an excess of the compound of formula (III). Since this reaction is a dehalogenated hydrogen reaction, it is necessary to capture this. Usually, this object can be achieved by using an excessive amount of the compound of the formula (III), but separately an alkali metal, alkaline earth metal hydroxide, carbonate, etc. It may be used as. The reaction time varies depending on the temperature, but is usually 2 to 20 hours, preferably 5 to 10 hours.

Example 1

A mixture of 4.7 g of 1- (3'-chloropropoxy) -2,4-bis (2 "-methoxybenzamido) -benzene, 30 ml of dioxane and 10 cc of 40% dimethylamine aqueous solution was added at 90 to 100 ° C. After stirring, add 5 cc of 40% aqueous dimethylamine solution and stir at the same temperature for 3 hours, and after cooling, add water, extract with benzene, add dilute hydrochloric acid, collect the water layer, and wash with ether. The mixture was extracted with benzene using potassium carbonate at a pH of 9 to 10. The benzene layer was washed with water, dried and concentrated, and the residue was purified by silica gel column chromatography (solvent with benzene-methanol mixed solvent) and benzene-hexane mixed solvent. Recrystallization was carried out to obtain 3.1 g of 1- (3'-dimethylaminopropoxy) -2,4-bis (2 "-methoxybenzamido) -benzene. Melting point 128-129 degreeC.

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

Theoretic value (%): C 67.9 H 6.5 N 8.8

Found (%): C 68.1 H 6.7 N 8.8

Example 2

A mixture of 4.7 g of 1- (3'-chloropropoxy) -2,4-bis (2 "-methoxybenzamido) -benzene, 20 ml of 1-butanol and 8 g of diethylamine was heated to reflux for 6 hours. After cooling, water was added, extraction was performed with benzene, the benzene layer was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography, eluted with a benzene-methanol mixed solvent), and recrystallized with a benzene-hexane mixed solvent. 2.5 g of-(3'-diethylaminopropoxy) -2,4-bis (2 "-methylbenzamido) -benzene was obtained. Melting Point 99-100 ℃

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

Theoretic value (%): C 73.5 H 7.5 N 8.9

Found (%): C 73.4 H 7.7 N 8.8

Example 3

A mixture of 4.5 g of 1- (3'-bromopropoxy) -2,4-bis (benzamido) -benzene, 20 ml of toluene and 8 g of diethylamine was heated to reflux for 5 hours, in the same manner as in Example 2 below. After the treatment, 2.4 g of 1- (3'-diethylaminepropoxy) -2,4-bis (benzamido) -benzene was obtained by recrystallization with a methanol-water mixed solvent. Melting Point 139 ~ 140 ℃

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

Theoretic value (%): C 72.8 H 7.0 N 9.4

Found (%): C 72.7 H 7.2 N 9.3

Example 4

1- (2'-bromoethoxy) -2,4-bis (2 "-methylbenzamido) -benzene was condensed with morpholine in the same manner as in Example 3, and treated in the same manner below, to benzene- It recrystallized with the ether mixed solvent and obtained 1- [2-N monopoly- ethoxy] -2, 4-bis (2 "-methyl benzamido) -benzene. Yield 54%, Melting Point 80-81 ° C

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

Theoretic value (%): C 71.0 H 6.6 N 8.9

Found (%): C 71.1 H 6.8 N 8.9

Example 5

In the same manner as in Example 2, 1- (3'-chloropropoxy) -2,4-bis (2 "-methoxy-4" -methylbenzamido) -benzene was reacted with diethylamine, the same as below. After the treatment, the mixture was recrystallized with methanol to obtain 1- (3'-diethylaminopropoxy) -2,4-bis (2 "-methoxy-4" -methylbenzamido) -benzene. Yield 49%, Melting point 127-129 degreeC (decomposition)

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

Theoretic value (%): C 69.8 H 7.4 N 7.9

Found (%): C 69.7 H 7.7 N 8.0

Example 6

In the same manner as in Example 1, 1- (3'-chloropropoxy) -2,4-bisi (2 ", 3" -dimethoxybenzamido) -benzene was reacted with diethylamine and treated in the same manner below. After recrystallization with ethanol, 1- (3'-dimethylaminopropoxy) -2,4-bis (2 ", 3" -dimethoxybenzamido) -benzene was obtained. Yield 55%, Melting point 131-132 degreeC

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

Theoretic value (%): C 64.8 H 6.6 N 7.8

Found (%): C 64.6 H 6.8 N 7.7

Example 7

In the same manner as in Example 2, the reaction was carried out with 1- (2'-chloroethoxy) -2,4-bis (2 "-ethoxybenzamido) -benzene and diethylamine. Dissolved in water and inhaled with hydrogen chloride gas to precipitate hydrochloride, which is separated and recrystallized with ethanol to give 1- (2'-diethylaminoethoxy) -2,4-bis (2 "-ethoxybenzamido)-. Benzene hydrochloride was obtained. Yield 55%, Melting point 194-195 degreeC

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

Theoretic value (%): C 64.8 H 6.9 N 7.6

Found (%): C 64.9 H 7.0 N 7.5

Example 8

1- (3'-bromopropoxy) -2,4-bis (2 "-methylbenzamido) -benzene was reacted with piperidine in the same manner as in Example 3, and then treated in the same manner below. The crystals were recrystallized from an ether-petroleum ether mixed solvent to obtain 1- [3- (N-piperidino) -propoxy] -2,4-bis (2 "-methylbenzamido) -benzene. Yield 64%, Melting Point 77-80 ° C

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

Theoretic value (%): C 73.5 H 7.5 N 8.9

Found (%): C 73.6 H 7.7 N 9.1

Example 9

In the same manner as in Example 1, 1- (4'-bromobutoxy) -2,4-bis (3'-methylbenzamido) -benzene was reacted with dimethylamine, and then treated in the same manner, and then to benzene. Recrystallization with an ether mixed solvent yielded 1- (4'-dimethylaminobutoxy) -2,4-bis (3 "-methylbenzamido) -benzene. Yield 61%, Melting point 105-107 degreeC

Elemental Analysis Value: C ₂₈ H ₂₃ N ₃ O ₃

Theoretic value (%): C 73.2 H 7.2 N 9.1

Found (%): C 73.1 H 7.5 N 9.1

Example 10

1- (3'-chloropropoxy) -2,4-bis (4 "-methylbenzamido) -benzene was reacted with dimethylamine in the same manner as in Example 1, and then treated in the same manner below, followed by methanol Recrystallization was carried out to obtain 1- (3'-dimethylaminopropoxy) -2,4-bis (4 "-methylbenzamido) -benzene. Yield 61%, Melting Point 163-164 ° C

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

Theoretic value (%): C 72.8 H 7.0 N 9.4

Found (%): C 72.7 H 7.2 N 9.5

Example 11

In the same manner as in Example 3, 1- (3′-bromopropoxy) -2,4-bis (3 ″ -methylbenzoamido) -benzene was reacted with dimethylamine, and then treated in the same manner below. Recrystallization with -ether gave 1- (3'-dimethylaminopropoxy) -2,4-bis (3 "-methylbenzamido) -benzene. Yield 67%, Melting Point 120-121 ° C

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

Theoretic value (%): C 72.8 H 7.0 N 9.4

Found (%): C 73.1 H 7.1 N 9.3

Example 12

In the same manner as in Example 3, 1- (3'-bromopropoxy) -2,4-bis (2 "-methylbenzamido) -benzene was reacted with dimethylamine, and the same treatment was carried out in the following. Recrystallization was carried out from -ether to obtain 1- (3'-dimethylaminopropoxy) -2,4-bis (2 "-methylbenzamido) -benzene. Yield 63%, Melting Point 136-137 ° C

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

Theoretic value (%): C 72.8 H 7.9 N 9.4

Found (%): C 72.7 H 6.9 N 9.6

Claims (1)

General formula

In the formula, Hal represents a halogen atom, X and Y are the same or different, and a hydrogen atom, a lower alkyl group, a lower alkoxy group, and A represents a lower alkylene group.

Reacting with a compound represented by (wherein, R ₁ and R ₂ are the same or different and are lower alkyl groups and, optionally, R ₁ and R ₂ may be bonded to each other directly or through a heteroatom). General formula

The manufacturing method of the benzanilide derivative represented by (wherein X, Y, A, R <_1> , R <_2> has the meaning of the former).