KR20010083487A - Process for producing sofalcone - Google Patents

Abstract

The present invention relates to 4- (3-methyl-2-butenyloxy) -benzaldehyde of formula (2) and 2-carboxymethoxy-4- (3-methyl-2-butenyloxy) of formula (3) -A method for producing sofalcone represented by the following formula (1) by reacting acetophenone in the presence of a weakly acidic alkali metal salt catalyst:

Description

Process for producing sofalcone

The present invention relates to Sofalcone, which is a peptic anti-ulcer agent having the structure of Formula (1).

Several methods have been reported for preparing sofalcone.

U.S. Patent No. 4,085,135 discloses 4- (3-methyl-2-butenyloxy) -benzaldehyde and 2-ethoxycarbonylmethoxy-4- (3-methyl-2-butenyloxy) -acetophenone A method for preparing sofalcone by aldol condensation using an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide in an ethanol mixed solution is described:

In addition, Japanese Patent Application Laid-Open No. 2-33024 uses a 2-hydroxy chalcone derivative to react with bromoethyl acetate in a solvent such as acetone or dimethylformamide using an alkali metal hydroxide such as potassium hydroxide and quaternary ammonium iodine as catalysts. Described is a method of making a falcon.

However, when preparing a falcon according to US Patent No. 4,085,135, the reaction rate is slow, and the overall yield is low as 60% or less. In general, a method of preparing α, β-unsaturated ketone derivatives by aldol condensation reaction is known to be the most efficient method of reacting in a sodium hydroxide aqueous solution and an ethanol basic mixed solution. When reacting acetophenone and a benzaldehyde derivative substituted with an alkoxy group at the 2 or 4 position, the alkoxy group is less reactive as an electron-withdrawing functional group. Therefore, the alkali metal salt must be used at least 20 equivalents to improve the reactivity. In this case, when an excess of base is used, side reactions are relatively easy to occur, and thus, there is a disadvantage in decreasing yield and purity.

In addition, when prepared according to Japanese Patent Application Laid-Open No. 2-33024, further purification since cyclic derivatives are formed as impurities by intramolecular reaction of α, β-unsaturated ketone group and 3-methyl-2-butenyloxy group of sofalcone. There are disadvantages in the process and the yield is poor to go through the process.

Thus, the present inventors have conducted a number of studies to solve the problems of the prior art, when producing a falcon using a weakly acidic alkali metal salt as a catalyst, the yield is high by the effect of keeping the pH of the reaction solution constant The present invention was completed by finding that the formation of by-products is small.

Accordingly, it is an object of the present invention to provide a production method useful for making falcon.

The present invention is described in detail as follows.

The present invention relates to 4- (3-methyl-2-butenyloxy) -benzaldehyde represented by the following general formula (2) and 2-carboxymethoxy-4- (3-methyl-2-butenyloxy of the following general formula (3). The present invention relates to a method for producing sofalcon, which is a chalcone derivative represented by formula (1), by reacting a) -acetophenone in the presence of a weakly acidic alkali metal salt catalyst.

The method for preparing the falfalcon of the present invention is shown in the following scheme:

The weakly acidic alkali metal salt used in the reaction is preferably potassium carbonate, sodium phosphate, potassium cyanide, or the like, more preferably sodium phosphate.

It is preferable to use 3-10 mol per mole of the compound of General formula (3), and, as for the weakly acidic alkali metal salt used for the said reaction, it is more preferable to use 5-8 mol.

In addition, it is preferable to use 30% methanol or ethanol aqueous solution as the solvent used in the preparation method of the present invention, and the reaction temperature and the reaction time are preferably 10 to 100 ° C. and about 3 to 8 hours, more preferably. Are 20-50 ° C. and 5 hours, respectively. If the temperature is lower than the reaction temperature, the reactivity is lowered. If the temperature is higher than the reaction temperature, a side reaction occurs. If the time is shorter than the reaction time, the reaction yield is lowered. If the time is longer than the reaction time, the reaction time is not improved. Because it is longer, the economy is less. When the reaction is completed, the reaction solution is acidified using dilute hydrochloric acid, and the solid produced is filtered and then purified to obtain high-purity sofalcone.

EXAMPLE

Hereinafter, preferred examples and comparative examples are presented to aid the understanding of the present invention. However, the following examples are merely provided to more easily understand the present invention, and the present invention is not limited to the following examples.

Example 1 Preparation of Sofalcone

30 g of 2-carboxymethoxy-4- (3-methyl-2-butenyloxy) -acetophenone was added to a reaction solvent in which 40 g of sodium phosphate was dissolved in 200 ml of a 30% ethanol aqueous solution, and stirred at room temperature for 30 minutes. 20 g of 4- (3-methyl-2-butenyloxy) -benzaldehyde was added, and the temperature was raised to 40 ° C to react for 5 hours.

When the reaction was completed, the reaction mixture was acidified with diluted aqueous hydrochloric acid solution, stirred for 30 minutes, and the resulting yellow crystalline solid was filtered and recrystallized in ethanol to give 44 g of the target compound as yellow crystals (yield: 92%) .

¹ H-NMR (CDCl ₃ , ppm): 1.74 (12H, s), 4.53 (4H, d), 4.73 (2H, s), 5.48 (2H, t), 6.50 (1H, d), 6.62 (1H, d), 6.90 (2H, d), 7.51 (2H, d), 7.64 (1H, d), 11.82 (1H, s).

Examples 2-3: Preparation of Sofalcone

Except that the amount of sodium phosphate used in Table 1 (the equivalent used is based on 2-carboxymethoxy-4- (3-methyl-2-butenyloxy) -acetophenone) was changed. Sofalcon was prepared using the same process as in Example 1.

Example Sodium Phosphate Usage (g / equivalent) Response time (hours) yield(%) Example 2 33/5 6 90 Example 3 53/8 5 91

Comparative Example 1

15 g of 2-ethoxycarbonylmethoxy-4- (3-methyl-2-butenyloxy) -acetophenone and 4- (3-methyl-2-part) according to the method described in US Pat. No. 4,085,135. Tenyloxy) -benzaldehyde was dissolved in 50 ml of ethanol, and 100 ml of a 20% aqueous potassium hydroxide solution was added thereto, followed by stirring at room temperature for 4 hours.

When the reaction was completed, the reaction mixture was acidified with dilute hydrochloric acid, extracted with ether, the ether was distilled off, and recrystallized from ethanol to give 11.9 g of the target compound as yellow crystals (yield: 54%).

According to the production method of the present invention, it is possible to obtain the falcon with higher purity and higher yield than the conventional method, and thus the production method is very easy for industrial production.

Claims (3)

4- (3-methyl-2-butenyloxy) -benzaldehyde of the formula (2) and 2-carboxymethoxy-4- (3-methyl-2-butenyloxy) -acetophenone of the formula (3) To react Sofacon of Formula (1) by reacting in the presence of a weakly acidic alkali metal salt catalyst: The method of claim 1 wherein said weakly acidic alkali metal salt is sodium phosphate. The method of claim 2, wherein said sodium phosphate is 5 to 8 equivalents.