JPS6154016B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the general formula () (wherein, X represents a halogen atom, m represents an integer of 1 to 3, and n represents an integer of 0 to 1). The present inventors have previously synthesized many anthranilic acid derivatives and studied their pharmacological effects, and found that they have remarkable anti-inflammatory and anti-allergic effects, and are currently applying for a patent.
52-134941 (Unexamined Japanese Patent Publication No. 1983-66649), Patent Application No. 1973-
31884 (Japanese Unexamined Patent Application No. 132544 of 1972), Patent Application No. 149200 of 1977
(Japanese Patent Application Laid-Open No. 55-76852)). The carboxylic acid amide derivative in the present invention is a new compound that has not been described in any literature, and is also an important intermediate for producing anthranilic acid derivatives. It is also an industrially useful compound that has pharmacological effects such as anti-allergic, anti-inflammatory, analgesic, and sedative effects. The compound of the present invention can be obtained in good yield by the method shown in the reaction formula below, but these production methods are only examples, and of course it can also be produced by other chemically similar methods. be. Production method A method in which a compound represented by the general formula () is reacted with benzoic acid represented by the general formula () or a reactive derivative thereof. (wherein, under solvent,
Alternatively, a heating dehydration reaction may be carried out in an organic solvent such as toluene, xylene, ethylene glycol or diethylene glycol, or a dehydrating agent (sulfuric acid,
To obtain the target compound in good yield by carrying out the reaction in an organic solvent such as ether, dichloromethane, dichloroethane, benzene, toluene, xylene, etc., in the presence of phosphorus pentoxide, polyphosphoric acid, dicyclohexylcarbodiimide, etc.) at room temperature or under heating. I can do it. Also, reactive derivatives of benzoic acid represented by the general formula () (e.g. acid halides, acid anhydrides)
may be reacted at room temperature or under heating in an organic solvent such as tetrahydrofuran, acetone, chloroform, pyridine, benzene, toluene, or xylene.
Further, when using an acid halide, the reaction proceeds quickly if a deoxidizing agent (eg, trimethylamine, triethylamine, pyridine, sodium carbonate, potassium carbonate, etc.) is used. The carboxylic acid amide derivative obtained by the present invention can be heated in a solvent such as pyridine, water, or acetic acid in the presence of 2 to 3 times the molar amount of an oxidizing agent (e.g., potassium permanganate) to increase the yield. Anthranilic acid derivatives can be easily obtained. EXAMPLES The present invention will be explained in more detail with reference to Examples below. Example 1 A mixture of 2.1 g of 3,4,5-trimethoxybenzoic acid, 15 ml of dry benzene, and 2 ml of thionyl chloride was
After refluxing for an hour, the solvent was distilled off under reduced pressure. The residue was dissolved in 10 ml of dry tetrahydrofuran, added to a mixed solution of 1.4 g of 6-chloro-o-toluidine, 15 ml of dry tetrahydrofuran, and 1.5 ml of triethylamine, and stirred at room temperature for 2 hours. Next, the solvent was distilled off under reduced pressure, water was poured into the residue to obtain the product, and after drying, recrystallization from ethanol resulted in colorless prismatic crystals of 3,4,5-trimethoxybenzoyl-6-chloro-o. - Obtained 3.1g of toluidide. The melting point, infrared absorption spectrum, mass spectrum, and elemental analysis values of this substance were as follows. Melting point 165-167℃ Infrared absorption spectrum υc=o(KBr) 1630cm
^-1 Mass spectrum M ⁺ 335 Elemental analysis value C ₁₇ H ₁₈ CNO ₄ Theoretical value C: 60.81 H: 5.40 N: 4.17 Actual value C: 60.74 H: 5.47 N: 4.23 Example 2 3,4,5-trimethoxy A mixture of 2.1 g of benzoic acid, 15 ml of dry benzene, and 2 ml of thionyl chloride was
After refluxing for an hour, the solvent was distilled off under reduced pressure. The residue was dissolved in 10 ml of dry tetrahydrofuran, added to a mixed solution of 1.3 g of 4-fluoro-o-toluidine, 15 ml of dry tetrahydrofuran, and 1.5 ml of toluethylamine, and refluxed for 30 minutes. Next, water was poured into the solution to collect the precipitated crystals, and after drying, recrystallization from ethanol yielded 2.6 g of 3,4,5-trimethoxybenzoyl-4-fluoro-o-toluidide in the form of colorless needle-like crystals. Ta. The melting point, infrared absorption spectrum, mass spectrum, and elemental analysis values of this substance were as follows. Melting point 173-175℃ Infrared absorption spectrum νc=o(KBr) 1630cm
^-1 Mass spectrum M ⁺ 319 Elemental analysis value C ₁₇ H ₁₈ FNO ₄ Theoretical value C: 63.94 H: 5.68 N: 4.39 Actual value C: 63.83 H: 5.61 N: 4.46 Reference example 3,4,5-trimethoxy 7.0 g of benzoyl-5-chloro-o-toluidide was added to a mixed solution of pyridine and water (1:1), and 9.9 g of potassium permanganate was added in portions under reflux.
The mixture was further stirred under reflux for 15 hours. Next, the reaction mixture was filtered and the liquid was distilled off under reduced pressure. Add water to the residue, filter out insoluble matter, make the solution acidic with dilute hydrochloric acid under ice cooling, collect the precipitated crystals, dry and recrystallize from acetone to obtain colorless needle-shaped N-(3,4, 5.8 g of 5-trimethoxybenzoyl)-5-chloroanthranilic acid was obtained. The melting point and elemental analysis values of this substance were as follows. Melting point 273-275℃ Elemental analysis value C ₁₇ H ₁₆ CNO ₆ Theoretical value C: 55.82 H: 4.41 N: 3.83 Actual measurement value C: 55.87 H: 4.36 N: 3.92 Examples 3-7 Examples 1-2 The following compound was synthesized according to the method. 【table】

Claims (1)

[Claims] 1 General formula () A carboxylic acid amide derivative represented by the formula (wherein, X represents a halogen atom, m represents an integer of 1 to 3, and n represents an integer of 0 to 1).