KR920001768B1 - Process for preparing cromone carboxylate - Google Patents

Abstract

A process for preparing chromone carboxylate of formula (I) comprises (a) halobenzene of formula (II) or its nuclear substd. derivs. with oxaloacetic acid of formula (III) or its salts in an organic solvent at 20-80 deg.C, and (b) cyclizing the obtd. intermediate of formula (IV) in the presence of an acid catalyst. In the formulas, X=Cl, Br or F; R1 and R2 each = H or C1-4 alkoxy or alkyl; M=H or Na; R'=H or C1-3 alkyl. Pref. the organic solvent is chloroform, benzene, dioxane or toluene.

Description

Method for preparing chromone carboxylate

The present invention relates to a method for producing chromone carboxylate, and more particularly, chromone obtained by reacting a nucleosubstituted chlorobenzene with an ester of oxaloacetic acid and sodium salt to form an intermediate, followed by a condensation hydrolysis reaction. It relates to a method for producing a carboxylate.

In general, chromone carboxylic acid compounds having a high vitamin P potency and used for the treatment of vascular complications such as diabetes mellitus include nucleosubstituted 2-hydroxyacetophenone and dialkyloxalate under an alkali metal catalyst such as ether, dioxane and ethanol. It is prepared by carrying out the condensation reaction by adding to an organic solvent of, followed by a continuous cyclization reaction and a hydrolysis reaction. The following reaction mechanism is known.

Wherein X is a halogen atom.

That is, a chromone carboxylic acid compound is manufactured by reacting a salicylic acid methyl ester and a keto sulfoxide compound to form a (beta) -keto sulfoxide compound, and then reacting this with glyoxalic acid butyl ester again.

However, according to the conventional manufacturing method as described above, a large amount of ethoxy sodium salt must be used, and the reaction must be carried out under inert conditions with little moisture. In addition to being expensive, the process was difficult because of the high price of hydrochloric acid in the cyclization reaction to neutralize the sodium hydroxide produced as a by-product (reaction mechanism I).

In addition, it is difficult to handle because ketosulfoxide must be used, and it is cumbersome because the isomers are formed and separated during the reaction, and the yield is reduced.

The process of synthesizing chromo carboxylic acid using the starting material is the most commonly used process, there is a difficulty in the manufacturing process to use an excessive amount of a metal catalyst, there are problems such as inert conditions, high cost of the starting material.

Accordingly, the present invention overcomes the disadvantages of the process using 2-hydroxyacetophenone as a starting material, and thus uses chlorobenzene as a starting material to produce chromone carboxylic acid and its derivatives through mild reaction conditions. It is an object of the present invention to solve the conventional problems as described above and to provide a method for preparing chromone carboxylic acid with high purity and high yield.

Hereinafter, the present invention will be described in detail.

The present invention primarily reacts the halobenzenes of the following general formula (I) or its nuclear substituted derivatives with the oxaloacetic acid or its salts of the following general formula (II) at a temperature of 20 to 80 ° C in an organic solvent, After obtaining the intermediate of III), the intermediate is a method for producing a chromone carboxylate compound of the following general formula (IV) characterized in that the intermediate is subjected to a cyclization reaction under an acid catalyst.

Wherein X is Cl, Br or F, R ¹ and R ² are hydrogen or an alkoxy or alkyl group having 1 to 4 carbon atoms, M is hydrogen or sodium, and R 'is hydrogen or an alkyl group having 1 to 3 carbon atoms .

Referring to the present invention in more detail as follows.

The present invention is reacted by reacting the halobenzene of the general formula (III) or a nuclear substituted derivative thereof with the oxalo acetate ester of the general formula (IV) and salts thereof in an organic solvent such as chloroform, benzene, dioxane and toluene. To form an intermediate. At this time, the reaction temperature is from room temperature to 80 ℃, the reaction time varies depending on the type of the substituent, but approximately 2 to 5 hours is appropriate.

The compound of formula (V) thus produced was extracted, filtered and separated, dissolved in acid at a temperature of 100 ° C., and then heated and cyclized for 10 to 20 hours to produce the following formula (VI). The mon carboxylate is to be prepared. Here, the acid used includes chlor-FH sulfonic acid, polyphosphoric acid, sulfuric acid, and the like, and is preferably reacted under anhydrous reaction conditions.

Wherein X is a halogen element such as Br, Cl or F, R ¹ and R ² are hydrogen or an alkoxy or alkyl group having 1 to 4 carbon atoms, R 'is hydrogen or an alkyl group having 1 to 3 carbon atoms, and M is Hydrogen or a metal such as sodium, wherein the ethyl ester in the compound of formula (IV) may be located in either trans or cis.

When the reaction is completed, cold water is added to the reaction tank, the reaction solution is extracted with an organic solvent such as ethyl acetate, and then distilled under reduced pressure and dried to obtain chromone carboxylate.

The chromone carboxylate obtained here was heated at a temperature of 5 to 90 ° C. for 3 to 5 hours using a base such as potassium hydroxide or sodium hydroxide in a mixed solvent of water, methanol, ethanol, water and methanol, and water and ethanol. The temperature is then lowered and acidified, whereby the resulting solid can be filtered to obtain chromone carboxylic acid.

The present invention as described above is represented by a series of schemes as follows.

Wherein R ¹ and R ² are hydrogen or an alkoxy or alkyl group having 1 to 4 carbon atoms, R ′ is hydrogen or an alkoxy or alkyl group having 1 to 3 carbon atoms, X is a halogen atom, M is hydrogen or sodium In this case, the ethyl ester in the compound of the general formula (IV) may be located in either of trans and cis.

The compound synthesized according to the present invention is effective for treating hypertension and diabetic sinus vascular complications, and the administration drug may be a method of orally administering sodium salt or amine salt. Especially when R <^1> and R <^2> are hydrogen and they form a salt with diethylamine, it is useful as a therapeutic agent.

Comparing the method of the present invention with the conventional method, the process disadvantage of using a large amount of difficult alkoxy metal salts is solved, and chlorobenzene instead of using expensive 2-hydroxyacetophenone and its derivatives as starting materials. It is economical because it uses inexpensive compounds as starting materials, and side reactions are reduced during the reaction, and the by-products formed are salts, so it is easy to process, and it is possible to obtain chromone carboxylic acid with high purity and high yield. There is an advantage.

The present invention will be described in more detail based on the following examples.

Example 1

(A) 20 g of chlorobenzene was dissolved in 500 ml of dioxane, and 35 g of diethyl ester oxalo-acetate acetate was added dropwise thereto, followed by heating at 80 ° C. for 3 hours. When the reaction was completed, 200ml of water was added and extracted with ether, followed by removing water with magnesium sulfate, followed by filtration and distillation under reduced pressure to obtain a fumaric ester compound. The obtained fumaric ester compound was added to 200 g of poly formic acid, and then heated at a temperature of 100 ° C. for 12 hours. After the reaction was completed, the reaction mixture was added with cold water, the solution was extracted with ethyl acetate, the organic layer was washed with water, dried over magnesium sulfate, concentrated and dried under reduced pressure, and the oily chromo carboxylate was mixed with ether. After cooling to 0 ° C, needle-like white crystals were obtained (yield 85%).

(B) After dissolving 5 g of chromone carboxylate obtained in step (A) in ethanol, 10 ml of 2N aqueous sodium hydroxide solution was added and heated at a temperature of 80 ° C. for 3 hours. Upon completion of the reaction, the reaction solution was cooled to acidify and the resulting solid was filtered and dried to give chromone carboxylic acid (yield 82%).

ⅠR: ν _COOH 1735cm ^-1

Melting Point: 262 ~ 263 ℃

Purity: 99.0% (by titration method)

[Examples 2 to 4]

In the same manner as in Example 1, the compound shown in Table 1 was used, and the yield and melting point of the final chromone carboxylic acid are also shown in Table 1 below.

TABLE 1

Claims (2)

Next, a halobenzene of the general formula (I) or a nuclear substituted derivative thereof and the oxaloacetic acid or its salt of the following general formula (II) are first reacted at a temperature of 20 to 80 ° C. in an organic solvent to A method for producing a chromone carboxylate compound of the following general formula (IV), wherein the intermediate is subjected to a cyclization reaction under an acid catalyst after obtaining the intermediate.

Wherein X is Cl, Br or F, R ¹ and R ² are hydrogen or an alkoxy or alkyl group having 1 to 4 carbon atoms, M is hydrogen or sodium, and R 'is hydrogen or alkyl having 1 to 3 carbon atoms . The method of claim 1, wherein the organic solvent is chloroform, benzene, dioxane and toluene.