KR800000130B1 - Process for the preparing of new aminobenzoic acid derivatives - Google Patents

Abstract

Title compds. (I, R2,R3 = H, halogen, C1-6 lower alkyl), useful as anti-asthmatics, were prepd. by reaction of 2-halogeno benzoic acid derivs (II) with anthranylic acid or its derivs. at 120≰-150≰ for 3-5hr in solvent such as H2O, EtOH, BuOH, DMF, nitrobenzene, isoamyl alcohol, dimethylsulfoxide.

Description

Method for preparing new amino acid benzoic acid derivative

The present invention relates to a process for the preparation of the novel amino benzoic acid derivatives of the general formula (I).

Where

R ₂ and R ₃ represent a hydrogen atom, a halogen atom or a lower alkyl group having 1 to 6 carbon atoms, provided that R ₂ and R ₃ are not all hydrogen.

That is, when the present invention is described in detail, the compound of formula (I) is prepared by reacting the 2-halogeno benzoic acid derivative of formula (II) with anthranilic acid or anthranilic acid derivative of formula (III).

Where

R ₂ and R ₃ are as described above, and X represents a halogen atom.

All of the amino acid benzoic acid derivatives of the present invention are novel compounds and have good liver function improvement, immune function enhancement, normalization and antidepressant action, so that diseases caused by liver function improving agent and immune function incompleteness, for example, arterial rheumatism It can be used as a therapeutic agent for autoimmune diseases, cancer, bacterial infections, asthma and the like.

As an example of the amino acid benzoic acid derivative obtained by this invention, N-2'-carboxy-4'-chlorophenyl- anthranilic acid, N-2'-carboxy-4'-bromophenyl- anthranilic acid, N-2 ' -Carboxy-4'-methylphenyl- anthranilic acid, N-2'-carboxy-4'-ethylphenyl- anthranilic acid, N-2'-carboxy-4-butylphenyl- anthranilic acid, N-2'- Carboxyl-4'-Chlorophenyl-4-chloroanthranilic acid, N-2'-carboxyphenyl-4-chloroanthranilic acid, N-2'-carboxy-4'-methylphenyl-4-chloroanthranilic acid, N- 2′-Carboxyl-4′-ethylphenyl-4-chloroanthranilic acid, N-2′-carboxy-4′-propylphenyl-4-chloroanthranilic acid, N-2′-carboxy-4′-butyl Phenyl-4-chloroanthranilic acid, N-2'-carboxyphenyl-4'-bromoanthranilic acid, N-2'-carboxy-4'-chlorophenyl-4-bromoanthranilic acid, N-2 ' -Carboxy-4'-chlorophenyl-5-chloroanthranilic acid, N-2'-carboxy-5'-chlorophenyl-5-chloro Trinilic acid, N-2'-carboxyl-6'-methylphenyl-anthranilic acid, N-2'-carboxyl-6'-methylphenyl-4-chloroanthranilic acid, N-2'-carboxy-5'-methylphenyl -4-chloroanthranilic acid, N-2′-carboxyl-3′-methylphenyl-4-chloroanthranilic acid, N-2′-carboxy-3 ′, 6′-dimethylphenyl-4-chloroanthranilic acid, N -2'-carboxy-5'-chloro-6'-methylphenyl- anthranilic acid and N-2'-carboxyl-5'-chlorophenyl-4-chloro anthranilic acid are mentioned.

As 2-halogenobenzoic acid derivative (II) which is a raw material, 2-chloro-benzoic acid, 2, 4-dichloro-benzoic acid 2, 4-dibromo-benzoic acid, etc. are mentioned as an example of anthranilic acid derivative (III), for example. Anthranilic acid, 5-chloroanthranilic acid, 4-chloro-3-methylanthranilic acid, 3-methylanthranilic acid, 5-methylanthranilic acid, 3, 6-dimethylanthranilic acid and the like are used.

The reaction of 2-halogenobenzoic acid derivative (II) with anthranilic acid or anthranilic acid derivative (III) is carried out at a temperature of 25 ° C. or higher in the presence of a solvent, and generally 1 to 10 hours at 80 to 200 ° C., Preferably, it is performed in 120 to 150 degreeC for 3 to 5 hours. As the solvent, isoamyl alcohol, dimethyl sulfoxide, dimethylformamide, ethanol, butanol, n-amyl alcohol, diethylene glycol dimethyl ether, nitrobenzene, water and the like are used.

Anthranilic acid black or anthranilic acid derivative (III) is preferably used in excess of 2-halogenobenzoic acid derivative (II), and preferably 1.2 to 2.0 molar amount is used. In order to perform the reaction smoothly and increase the yield, it is preferable to use a reaction catalyst, and as the reaction catalyst, an alkali catalyst such as potassium carbonate, sodium carbonate, copper carbonate or the like is added in a molar amount or more, and metal copper powder, cuprous chloride, It is preferable to add metal compounds, such as copper and acetate acetate, to a brittle agent in catalytic amount, and when a catalytic amount of iodine compound is added, the quantity rises dramatically. As an iodine compound, iodine, sodium iodide, and copper oxylating agent are suitable, for example.

The aminobenzoic acid derivative (I) which is the object of the present invention can be made into an alkali metal salt such as sodium salt or potassium salt by a conventional method.

Example 1

250 ml of isoamyl alcohol, 12 g of 2,4-dichlorobenzoic acid, 17.5 g of anthranilic acid, 18 g of potassium carbonate, 500 mg of copper powder, and a small amount of iodine are placed in a 500 ml three-necked round flask equipped with a mechanical stirrer and a cooling tube. It is heated to reflux for 5 hours with stirring. After cooling the reaction mixture to room temperature, 500 ml of water was added and filtered. The mother liquor is concentrated under reduced pressure with water to remove isoamyl alcohol, cooled with ice water, and acidified with 6N hydrochloric acid to precipitate crystals. The crystals are suspended in methanol, heated to reflux for 3 to 4 hours, and filtered to cool the crystals. The crystals are further dissolved in tetrahydrofuran, activated carbon is added and refluxed for 4 to 5 hours, then activated carbon is removed and concentrated under reduced pressure. The resulting crystals are further suspended in methanol, heated to reflux for 3 to 4 hours, and the resulting crystals are filtered off to obtain 14 g of N-2'-carboxyphenyl-4-chloroanthranilic acid having a melting point of 340 ° C or higher. .

Elemental Analysis Value: C ₁₄ H ₁₂ Cl NO ₄

Example 2

When 2, 4-dichlorobenzoic acid and 5-methyl anthranilic acid were used, and others were processed similarly to Example 1, N-2'-carboxy-4'-methylphenyl-4-chloro of melting | fusing point 316-318 degreeC (decomposition) is carried out. Anthranilic acid is obtained.

Elemental Analysis Value: C ₁₅ H ₁₂ Cl NO ₄

Example 3

When 2-chloro-benzoic acid and 5-methyl anthranilic acid are used, and others are processed similarly to Example 1, N-2'-carboxy-4'- methylphenyl anthranilic acid of melting | fusing point 304 degreeC is obtained.

Elemental Analysis Value: C ₁₅ H ₁₃ NO ₄

Example 4

When 2, 4-dichloro-benzoic acid and 3-methyl anthranilic acid are used, and others are treated similarly to Example 1, N-2'-carboxyl-6'-methyl-phenyl- of melting | fusing point 302-304 (decomposition) is carried out. 4-chloroanthranilic acid is obtained.

Elemental Analysis Value: C ₁₅ H ₁₂ ClNO ₄

Example 5

When 2, 4-dichloro-benzoic acid and 4-chloro-andranilic acid are used, and others are processed similarly to Example 1, N-2'-carboxy-5'- chlorophenyl-4- chloroanthranyl of 340 degreeC or more of melting | fusing point is carried out. Acid is obtained.

Elemental Analysis Value: C ₁₄ H ₉ Cl ₂ NO ₄

Example 6

When 2, 4-dichloro-benzoic acid and 3, 6- dimethyl anthranilic acid are used, and others are processed similarly to Example 1, N-2'-carboxy-3 ', 6'- dimethyl-phenyl of melting | fusing point 283 degreeC is carried out. 4-chloroanthranilic acid is obtained.

Elemental Analysis Value: C ₁₆ H ₁₄ ClNO ₄

Example 7

When 2-chloro-benzoic acid and 4-chloro-3-methylanthranilic acid are used, and the others are treated in the same manner as in Example 1, N-2'-carboxyl-5'-chloro-6'-methylphenyl having a melting point of 315 占 폚 is used. Anthranilic acid is obtained.

Elemental Analysis Value: C ₁₅ H ₁₂ ClNO ₄

Example 8

When 2, 5- dichloro-benzoic acid and anthranilic acid are used and the others are processed similarly to Example 1, N-2'-carboxyphenyl-5-chloro anthranilic acid of the dew point of 310 degreeC is obtained.

Example 9

2.4 g of 2,4-dichlorobenzoic acid, 3.5 g of anthranilic acid, 3.6 g of anhydrous potassium carbonate and 0.4 g of copper powder are added to 50 ml of isoamyl alcohol, and the mixture is heated to reflux for 5 hours with stirring in a 200 ml flask. After the reaction is completed, the mixture is cooled to room temperature, and filtered by suction with water. The mother liquor was concentrated under reduced pressure with water to remove isoamyl alcohol, and the resulting crystals were collected by acidification with 6N hydrochloric acid. The crystals are dissolved in tetrahydrofuran to carry out activated carbon treatment, the activated carbon is removed, and then concentrated to remove tetrahydrofuran. Methanol was added to the residue, the mixture was heated to reflux, and cooled to room temperature, whereby 1.1 g of yellow amorphous N-2'-carboxyphenyl-4-chloroanthranilic acid having a melting point of 340 ° C or higher was obtained.

Example 10

110 g of N-2'-carboxyphenyl-4-chloro anthranilic acid is dissolved in 2 liters of 30 g of sodium hydroxide, and ethyl alcohol is added to this solution. 88 g of sodium salt of nitric acid is obtained.

Elemental Analysis Value: C ₁₄ H ₈ Na ₂ ClNO ₄

Claims (1)

A method for producing an aminobenzoic acid derivative of the general formula (I), wherein the 2-halogenobenzoic acid derivative of the general formula (II) is reacted with anthranilic acid or anthranilic acid derivative of the following formula (II).

Where R ₂ and R ₃ represent a hydrogen atom, a halogen atom or a lower alkyl group having 1 to 6 carbon atoms, provided that R ₂ and R ₃ are not all hydrogen, X represents a halogen atom.