JPS6345660B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel method for producing 3-acylsalicylic acid derivatives. 3-Methylflavone-8-carboxylic acid is useful as an intermediate raw material for pharmaceuticals, and in particular, its basic ester has come to be actually used as a pharmaceutical such as an agent for preventing frequent urination. This 3-methylflavone-8
- Various methods for producing carboxylic acids are known, one of which is a method using 3-propionylsalicylic acid as a raw material, as described in U.S. Patent No. 2921070, Japanese Patent Publication No. 51-4983, Japanese Patent Application Laid-open No. 49-80035, etc. Disclosed. These prior documents also describe several methods for producing 3-propionylsalicylic acid, but these methods have drawbacks such as long production steps and insufficiently high yields. The present inventors have discovered that 3-propionylsalicylic acid, such as 3-propionylsalicylic acid, is useful as an intermediate raw material for pharmaceuticals as described above.
As a result of investigating a method for producing a precursor that can be easily converted into acylsalicylic acid with high selectivity in a short process using readily available raw materials, the following method was discovered. That is, the present invention provides a 3-acylsalicylic acid derivative characterized in that 2-acylphenol is acetalized or ketalized and then reacted with carbon dioxide gas in the phenolate state. (R ₁ , R ₂ : hydrocarbon group, R: hydrogen or hydrocarbon group). The present invention uses 2-acylphenol as a raw material,
The Kolbe-Schmitt reaction is used to introduce a carboxyl group, but when performing this reaction directly on 2-acylphenol, it causes a ring-closing reaction, making it difficult to obtain the target compound. The carbonyl group is protected by prior acetalization or ketalization. Acetalization or ketalization can be carried out, for example, by reacting 2-acylphenol with alcohol, orthoformate, dimethylformamide acetal, or the like in the presence of an acid catalyst. Examples of the alcohol include polyhydric alcohols such as ethylene glycol, propylene glycol, neopentyl glycol, and glycerin, and orthoformic acid esters.
For example, methyl orthoformate, ethyl orthoformate, etc., and as the dimethylformamide acetal, dimethylformamide diethyl acetal, dimethylformamide ethylene acetal, etc. can be used. Most preferred is the use of glycols. As the acid catalyst, for example, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, protonic acids such as cation exchange resins, Lewis acids such as boron trifluoride/ether complex, etc. can be used. can. Acetalized or ketalized 2-acylphenol is converted into acetalized or ketalized 3-acylsalicylic acid by the Kolbe-Schmitt reaction. The reaction is carried out by reacting acetalized or ketalized phenolate of 2-acylphenol with carbon dioxide gas. At this time, it is desirable to carry out the reaction while dissolving or suspending the phenolate using a suitable diluent such as lower hydrocarbons, benzene, toluene, xylene, dioxane, dimethylformamide, etc. As the phenolate, sodium phenolate or potassium phenolate is preferred. The reaction temperature is preferably in the range of about 100 to 250°C. Also, the partial pressure of carbon dioxide gas is 1 to 100Kg/
cm ² , particularly in the range 10 to 50 Kg/cm ² . This reaction produces a salt of acetalized or ketalized 3-acylsalicylic acid, and when extracted under acidic conditions, a free 3-acylsalicylic acid derivative is obtained. 3-acylsalicylic acid can be easily obtained by hydrolyzing this 3-acylsalicylic acid derivative in the presence of an acid catalyst. As acid catalysts, sulfuric acid, para-toluenesulfonic acid, trifluoromethanesulfonic acid, cation exchange resins, protonic acids such as acetic acid, and Lewis acids such as boron trifluoride/ether complexes are used. Also, acetalized or ketalized 3-
When acylsalicylic acid is reacted with an alcohol in the presence of an acid catalyst, hydrolysis of the ketal group and esterification proceed simultaneously, yielding 3-acylsalicylic acid ester. In this reaction, for example, methanol, ethanol, propanol, butanol, etc. can be used as the alcohol. Hereinafter, this will be explained in detail using examples. Example 1 30.04 g (0.2 mol) of 2-propionylphenol, 37.24 g (0.6 mol) of ethylene glycol, 1.01 g (10 mol%) of concentrated sulfuric acid, and 150 ml of benzene
The mixture was placed in a 300 ml flask and azeotropically dehydrated for 12 hours with stirring. The reaction mixture was cooled, and ethyl acetate and aqueous sodium bicarbonate were added to separate the layers. The organic layer was washed with water, dried, and concentrated, and the residue was analyzed by gas chromatography. The conversion rate of 2-propionylphenol was 44%, and the yield of ethylene ketal was 44% (selectivity 100%). Examples 2 to 4 The same procedure as in Example 1 was performed except that the acids shown in Table 1 were used instead of the sulfuric acid in Example 1, and the results shown in Table 1 were obtained.

【table】

[Table] Examples 5 to 6 The same procedure as in Example 1 was performed except that the alcohol shown in Table 2 was used instead of the ethylene glycol in Example 1, and the results shown in Table 2 were obtained.

[Table] Example 7 The same procedure as in Example 1 was carried out except that 2-acetylphenol was used instead of 2-propionylphenol in Example 1. The conversion rate of 2-acetylphenol was 48%, and the conversion rate of ethylene ketal was 48%. Yield is 48
% (selection rate 100%). Example 8 3.89 g (0.02 mol) of 2-propionylphenol ethylene ketal was added to an ethanol solution containing 1.43 g (0.021 mol) of sodium ethoxide,
Ethanol was distilled off under reduced pressure, and the residue was heated to 5 mmHg.
Sodium phenolate was prepared by drying at 75°C under reduced pressure overnight. 3.24 g (0.015 mol) of the above sodium phenolate and 20 ml of dioxane were placed in a 100 ml stainless steel autoclave, and the atmosphere was replaced with carbon dioxide gas.The autoclave was then pressurized with carbon dioxide gas to an initial pressure of 20 kg/cm ² G, and a reaction was carried out at 160°C for 2 hours. . After cooling the reaction mixture, the pH was adjusted to 9.
~10, extracted with ethyl acetate, and after extraction 2-
Propionylphenol ethylene ketal 1.34g
was recovered (conversion rate 54%). On the other hand, the alkaline aqueous layer was acidified with dilute hydrochloric acid and extracted with ethyl acetate, and the organic layer was washed with water, dried, and concentrated to produce 1.00 g (yield 28%) of 3-propionylsalicylic acid ethylene ketal and its hydrolysis product 3-propionyl. A mixture containing 0.15 g (5% yield) of salicylic acid was obtained. Examples 9 to 13 After reacting with carbon dioxide gas in the same manner as in Example 8 except that the solvent shown in Table 3 was used instead of the reaction solvent dioxane in Example 8, 3- When methyl propionylsalicylate was used for analysis using gas chromatography, the results shown in Table 3 were obtained.

[Table] Example 14 Potassium salt instead of sodium salt in Example 8
The reaction was carried out in the same manner as in Example 8 except that 3.48 g (0.015 mol) was used, and when methyl 3-propionylsalicylate was used and gas chromatography analysis was performed, the conversion rate was
The yield was 30% and the selectivity was 53%. Example 15 4.73 g (0.02 mol) of 2-propionylphenol neopentyl glycol ketal was added to a methanol solution containing 1.39 g (0.021 mol) of caustic potash (85%), the methanol was distilled off under reduced pressure, and the residue was vacuumed at 5 mmHg. Potassium phenolate was prepared by drying at 75°C overnight. 4.11 g (0.015 mol) of the above potassium phenolate and 20 ml of dioxane were placed in a 100 ml stainless steel autoclave, and the atmosphere was replaced with carbon dioxide gas.The autoclave was then pressurized with carbon dioxide gas to an initial pressure of 20 kg/cm ² G, and a reaction was carried out at 160°C for 2 hours. . After cooling the reaction mixture, the pH was adjusted to 9-9.
10 and extracted with ethyl acetate, and 2.13 g of 2-propionylphenol neopentyl glycol ketal was recovered from the extract (conversion rate 40%). on the other hand,
The alkaline aqueous layer was acidified with dilute hydrochloric acid and extracted with ethyl acetate, and the organic layer was washed with water, dried, and concentrated to obtain 0.55 g (yield: 13%) of neopentyl glycol ketal 3-propionylsalicylate. Example 16 3.60 g (0.02 mol) of 2-acetylphenol ethylene ketal was added to an ethanol solution containing 1.43 g (0.021 mol) of sodium ethoxide, the ethanol was distilled off under reduced pressure, and the residue was heated under a reduced pressure of 5 mmHg.
Dry overnight at 75°C. 3.03 g (0.015 mol) of the above sodium salt and 20 ml of dioxane in a 100 ml stainless steel autoclave.
After replacing the mixture with carbon dioxide gas, the reactor was pressurized with carbon dioxide gas to an initial pressure of 20 kg/cm ² ·G, and the reaction was carried out at 160°C for 2 hours. When post-treatment was performed in the same manner as in Example 8, the conversion rate was 63%, the yield of 2-acetylsalicylic acid ethylene ketal was 38%, and the yield of 3-acetylsalicylic acid was 4%. Reference Example 1 Half of the mixture containing 2-propionylsalicylic acid ethylene ketal and 3-propionylsalicylic acid obtained in Example 8 was mixed with 30 g of water and ethanol.
30 g and 0.5 g of concentrated sulfuric acid were added, and the mixture was heated under reflux for 2 hours. Add 200 ml of water, extract with ethyl acetate, wash with water, dry and concentrate, and recrystallize the residue from benzene-hexane.
g (yield 30% based on sodium phenolate) was obtained. Reference Example 2 75g of methanol was added to the remaining half of the mixture containing ethylene ketal 3-propionylsactylate and 3-propionylsalicylic acid obtained in Example 8.
Then, 1 g of concentrated sulfuric acid was added and the mixture was heated under reflux for 5 hours. After neutralizing the sulfuric acid with 1.7 g of sodium bicarbonate, methanol was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with water, dried, concentrated, and the residue was distilled off under reduced pressure to obtain 0.53 g (yield: 34%) of methyl 3-propionylsalicylate.

Claims (1)

[Claims] 1. General formula A general formula characterized by acetalizing or ketalizing 2-acylphenol represented by (wherein R represents hydrogen or a hydrocarbon group) and then reacting it with carbon dioxide gas in the phenolate state. A method for producing a 3-acylsalicylic acid derivative represented by the formula (wherein R is the same as above, and R ₁ and R ₂ represent a hydrocarbon group).