JP2902128B2 - Method for acylating anthranilic acids - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an industrially convenient acylation process for anthranilic acids which gives a high yield. The acyl form of anthranilic acids produced by the present invention is useful as a drug or a pharmaceutical intermediate material,
For example, N- (3 ′, 4′-dimethoxycinnamoyl) anthranilic acid, which is useful as a therapeutic drug for diseases caused by allergies, can be mentioned.

[0002]

2. Description of the Related Art As an acylation method of anthranilic acids, various methods are known, and they are produced by a method generally used for peptide synthesis. For example, by reacting anthranilic acids and their esters with active derivatives of carboxylic acids, such as acid halides, acid anhydrides, mixed anhydrides, carboxylic azides, active esters of carboxylic acids, etc., or anthranilic acids and their esters And a carboxylic acid with a condensing agent such as carbodiimide, acetylenic ether, hexamethylphosphoramide and p-toluenesulfonic anhydride, triphenylphosphine and imidazole, carbodiimidazole, triphenylphosphine and halogenated carbon, diphenylphosphoryl azide There is known a method of producing by condensing in the presence of phosphorus oxychloride, phosphorus pentoxide, polyphosphoric acid and the like.

[0003]

However, when using anthranilic acids as a raw material for one of these methods,
Due to the effect of the free carboxyl group at the ortho position relative to the amino group of anthranilic acid, the yield of the target product is reduced and a by-product is given, and it is difficult to purify the target product. When an ester of anthranilic acids is used as one of the raw materials, such a drawback is considerably improved, but there are drawbacks in that a further step such as hydrolysis of the ester and desalting with an acid is required to obtain the desired product. Therefore, it was not satisfactory as an industrial production method.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to overcome the above-mentioned drawbacks. As a result, the present inventors converted an anthranilic acid having an unprotected carboxyl group and a carboxylic acid into an iminium salt (in an aprotic polar solvent). Vilsmeier reagent)
During the study of the reaction, the presence of an alkaline earth metal halide allows the target product to be produced in high yield, and the reaction conditions are moderated, there are few by-products, and the purification of the target product is extremely easy. They found something and completed the present invention. That is, the present invention provides a simple and industrially advantageous method for acylating anthranilic acids, which directly synthesizes the desired product in high yield from anthranilic acids and carboxylic acids without any pretreatment and protecting group. Things.
The anthranilic acids used in the present invention include anthranilic acid and chloroanthranilic acid (2-amino-4
-Chlorobenzoic acid, 2-amino-5-chlorobenzoic acid)
On the other hand, as the carboxylic acid, either an aliphatic carboxylic acid or an aromatic carboxylic acid may be used, and the reaction is suitably carried out. Particularly preferred is a cinnamic acid derivative. The present invention is carried out in the presence of an iminium salt (Vilsmeier reagent) formed from dimethylformamide and an acid halide type reagent and an alkaline earth metal halide. Examples of the acid halide type reagent to be used include thionyl chloride, acetyl chloride, benzoyl chloride, cyanuric chloride, phosphorus oxychloride and the like, and thionyl chloride and phosphorus oxychloride are preferred. The acid halide-type reagent is preferably used in an equimolar amount, for example, 0.9 to 1.2-fold mol with respect to one of the starting carboxylic acids. On the other hand, examples of the alkaline earth metal halide include various salts, for example, magnesium chloride (anhydrous), calcium chloride (anhydrous), magnesium bromide (anhydrous) and the like are preferable. Double molar use is desirable. In this reaction, when an acylation reaction is generally performed using an iminium salt, a basic substance (tertiary amine, alkali) used to prevent a decrease in yield due to a by-produced acid is not required. The reaction is carried out in the presence of a solvent, but the solvent used includes an aprotic polar solvent,
For example, dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like can be mentioned, among which dimethylformamide is preferable. Reaction temperature is 0-50 °
C, The reaction time depends on the reaction conditions, but is about 30 minutes to several hours. The desired product after completion of the reaction can be obtained by adding water to the reaction solution, collecting the precipitated crystals by filtration, or concentrating the reaction solution under reduced pressure, and using an appropriate solvent such as ethanol or ethanol-water to concentrate the residue. It is easily implemented by crystallization. The feature of the present invention resides in that a target compound is directly synthesized in high yield in the presence of an alkaline earth metal halide using a highly active iminium salt quantitatively generated from dimethylformamide and an inexpensive acid halide type reagent. . Alkaline earth metal halides form a coordination bond between the amino group of anthranilic acids and the carbonyl oxygen of the carboxyl group, which has never been known before, and contributes to the condensation reaction of the free carboxyl group at the ortho position of anthranilic acids. Eliminating the adverse effects that occur, giving the desired product in high yield with almost no by-product formation, and despite the reaction to produce an acid, a basic substance or a neutral substance that can only neutralize the acid according to known conditions The fact that there is no need to use an excess of the amine component is a completely unexpected result from the prior art.

[0005]

The present invention will be described in detail below with reference to examples. Example 1 0.78 ml of thionyl chloride and 2.08 g of 3 ', 4'-dimethoxycinnamic acid were added in this order to 10 ml of dimethylformamide while cooling with ice water and stirring. This solution was slowly added dropwise to a solution of 2.0 g of anthranilic acid and 2.3 g of calcium chloride (anhydrous) dissolved in 15 ml of dimethylformamide while cooling with ice water and stirring. After dropping, at the same temperature 30
For 1 minute at room temperature. 80 ml of ice water after the reaction
After introducing air for 30 minutes, the precipitated crystals were collected by filtration and recrystallized from ethanol-water (1: 2) to give N- (3 ′, 4′-dimethoxycinnamoyl) anthranilic acid 2 0.35 g (71.8% yield) was obtained. Melting point 2
09-211 ° C. The structure of this compound was confirmed by a fusion test with a standard sample and a comparison of an infrared absorption spectrum. Example 2 To 10 ml of dimethylformamide, 0.78 ml of thionyl chloride and 2.08 g of 3 ', 4'-dimethoxycinnamic acid were added in this order while stirring with cooling with ice water. This solution was slowly added dropwise to a solution of 2.0 g of anthranilic acid and 3.2 g of magnesium chloride (anhydrous) dissolved in 15 ml of dimethylformamide with heating and cooling to room temperature while stirring at room temperature. After the completion of the dropwise addition, the mixture was continuously stirred for 1 hour. Thereafter, the same treatment as in Example 1 was performed to obtain 2.99 g (yield: 91.3%) of N- (3 ′, 4′-dimethoxycinnamoyl) anthranilic acid. Melting point 209-211 [deg.] C. The structure of this compound was confirmed by a fusion test with a standard sample and a comparison of an infrared absorption spectrum. Example 3 0.98 ml of phosphorus oxychloride, 6,7-dimethoxy-2-, in 15 ml of dimethylformamide under ice water cooling and stirring.
2.95 g of naphthoic acid were added in this order. 2.0 g of anthranilic acid in 15 ml of dimethylformamide,
To a solution of 3.2 g of magnesium chloride (anhydrous) dissolved under heating and cooled to room temperature was gradually added dropwise with stirring at room temperature. After completion of the dropwise addition, the mixture was continuously stirred for 1 hour. 80 ml of ice water after the reaction
Was added, and the mixture was stirred sufficiently. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 2.95 g of N- (6,7-dimethoxy-2-naphthoyl) anthranilic acid (yield: 84.0%). Obtained. 243-245 ° C. The structure of this compound was confirmed by a fusion test with a standard sample and a comparison of an infrared absorption spectrum. Example 4 In 10 ml of dimethylformamide, 0.78 ml of thionyl chloride and 2.05 g of α-acetamidocinnamic acid were added in this order while cooling with ice water and stirring. This solution was slowly added dropwise with stirring at room temperature to a solution of 2.0 g of anthranilic acid and 3.2 g of magnesium chloride (anhydrous) dissolved in 15 ml of dimethylformamide under heating and cooled to room temperature. After completion of the dropwise addition, the mixture was continuously stirred for 1 hour. Thereafter, by treating in the same manner as in Example 1, N- (α-acetamidocinnamoyl)
2.91 g (89.8% yield) of anthranilic acid were obtained.
Melting point 221-222 [deg.] C. The structure of this compound was confirmed by a fusion test with a standard sample and a comparison of an infrared absorption spectrum. Example 5 In 15 ml of dimethylformamide, 0.78 ml of thionyl chloride and 2.19 g of 4-pentylcinnamic acid were added in this order under cooling with ice water and stirring. This solution was slowly added dropwise to a solution obtained by dissolving 2.0 g of anthranilic acid and 3.2 g of magnesium chloride (anhydrous) in 15 ml of dimethylformamide and cooling to room temperature while stirring at room temperature. After completion of the dropwise addition, the mixture was continuously stirred for 1 hour. Thereafter, the same treatment as in Example 1 and recrystallization from ethanol gave 2.92 g of N- (4-pentylcinnamoyl) anthranilic acid (yield: 86.4).
%). Melting point 172-174 [deg.] C. The structure of this compound was confirmed by a fusion test with a standard sample and a comparison of an infrared absorption spectrum. Example 6 In 15 ml of dimethylformamide, 0.78 ml of thionyl chloride and 2.54 g of 4- (4-phenylbutyl) benzoic acid were added in this order while cooling with ice water and stirring. 2.5 g of 2-amino-5-chlorobenzoic acid and 3.2 g of magnesium chloride (anhydrous) were added to this solution in 15 ml of dimethylformamide.
Was slowly dissolved and dropped into the solution cooled to room temperature while stirring at room temperature. After completion of the dropwise addition, the mixture was continuously stirred for 1 hour. Thereafter, the same treatment as in Example 1 and recrystallization from ethanol gave 3.49 g of 2- [4- (4-phenylbutyl) benzoylamino] -5-chlorobenzoic acid (yield 85.50 g).
7%). 214-216 ° C. The structure of this compound was confirmed by a fusion test with a standard sample and a comparison of an infrared absorption spectrum. Example 7 In 15 ml of dimethylformamide, 0.78 ml of thionyl chloride and 2.8 g of 4- (4-phenylbutyl) cinnamic acid were added in this order while cooling with ice water and stirring. This solution was mixed with 2.5 g of 2-amino-5-chlorobenzoic acid and 3.2 g of magnesium chloride (anhydrous) in 15 ml of dimethylformamide.
Was slowly dissolved and dropped into the solution cooled to room temperature while stirring at room temperature. After completion of the dropwise addition, the mixture was continuously stirred for 1 hour. Thereafter, the mixture was treated in the same manner as in Example 1 and recrystallized from ethanol to give 3.68 g of 2- [4- (4-phenylbutyl) cinnamoylamino] -5-chlorobenzoic acid (yield 85.50 g).
0%). 202-204 ° C. The structure of this compound was confirmed by a fusion test with a standard sample and comparison of infrared absorption spectra.

[0006]

As described above, according to the method of the present invention, an anthranilic acid and a carboxylic acid are mixed with an iminium salt (Vilsmeier reagent) and an alkaline earth metal halide in an aprotic polar solvent. By carrying out the lower reaction, an acylated product of anthranilic acids, which is the target product, can be directly produced without a by-product in a high yield and without any need for any protecting group or pretreatment.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C 235/66 C07C 235/66 237/22 237/22 // C07B 61/00 300 C07B 61/00 300

Claims (1)

(57) [Claims] 1. An aprotic polar solvent in which an anthranilic acid and a chloroanthranilic acid are reacted with a carboxylic acid using an iminium salt (Vilsmeier reagent) in the presence of an alkaline earth metal halide. A method for acylating anthranilic acids.