KR19990015053A - Method for preparing 2- (4-halomethylphenyl) propionic acid - Google Patents

Abstract

A method of synthesizing 2- (4-halomethylphenyl) propionic acid with a short reaction path and high purity by reacting industrially readily available 2-phenylpropionic acid of formula (2) with a hydroformylating agent in the presence of a halometal and a phase transfer catalyst and an acid to provide.

[Compound 1]

[Compound 2]

Wherein X is selected from the group consisting of chlorine, bromine and iodine.

Description

Method for preparing 2- (4-halomethylphenyl) propionic acid

The present invention relates to a method for preparing 2- (4-halomethylphenyl) propionic acid, and more particularly, to a method for preparing 2- (4-halomethylphenyl) propionic acid, which is an intermediate useful for preparing propionic acid-based anti-inflammatory analgesics. will be.

[Formula 1]

In which X is selected from the group consisting of chlorine, bromine and iodine.

2- (4-halomethylphenyl) propionic acid is a useful intermediate for the preparation of propionic acid-based anti-inflammatory analgesics, and various attempts to prepare the same have been reported. According to the methods described in Japanese Patent Publication Nos. 87-129250 and 87-155237, 2- (4-halomethylphenyl) propionic acid can be prepared by reacting 2- (4-methylphenyl) propionic acid in the presence of active halogen. have. In addition, the 2- (4-halomethylphenyl) propionic acid production method described in Japanese Patent Publication No. 81-13840 is to react 2-phenylpropionic acid with methial in the presence of aluminum chloride (AlCl ₃ ) and tin chloride (SnCl ₄ ). .

However, according to the above method, when preparing 2- (4-halomethylphenyl) propionic acid, there are various problems in the manufacturing process. In other words, when the halogenation reaction is performed using an active halogen, not only the synthesis of the starting material needs to be carried out through several steps but also a byproduct of the radical reaction is generated simultaneously, thus requiring a difficult purification process to remove the halogenated reaction. .

On the other hand, when 2-phenylpropionic acid is reacted with methial in the presence of strong Lewis acids such as AlCl ₃ and SnCl ₄ , a large amount of by-products such as a diaryl compound and undesired 2- (2-halomethylphenyl) propionic acid are produced. However, it does not provide satisfactory results in terms of purity. For this reason, it is difficult to use known methods industrially, and development of more improved methods is required.

Accordingly, an object of the present invention is to provide a method for synthesizing 2- (4-halomethylphenyl) propionic acid with a short reaction path and high purity using industrially readily available 2-phenylpropionic acid as a starting material.

In order to achieve the above object, the present inventors have conducted a long continuous study, and then reacting 2-phenylpropionic acid of formula (2) with a hydroformylating agent in the presence of a halometal, a phase transfer catalyst, and an acid. Prepare (4-halomethylphenyl) propionic acid.

[Formula 1]

[Formula 2]

Wherein X is selected from the group consisting of chlorine, bromine and iodine.

The halometal used in the reaction includes sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium bromide, potassium bromide, calcium bromide, magnesium bromide, sodium iodide, potassium iodide, calcium iodide, magnesium iodide and the like, and the addition amount is a starting material. 1 to 10 equivalents are preferred, and most preferably 4 to 8 equivalents, relative to the compound of formula (2). At this time, when the addition amount of the halometal is less than the above range, the reaction does not occur smoothly, and when it exceeds the above range, the production cost increases and there is no economy.

Phase transfer catalysts used include tetraethylammonium halide, benzyltrimethylammonium halide, tetradecyltrimethylammonium halide, hexadecyltrimethylammonium halide, tetrabutylammonium chloride, tetrabutylammonium bromide and the like. And the like. The amount used is preferably 0.01 to 2 equivalents, most preferably 0.1 to 1 equivalents based on the compound of formula (2) as the starting material. In this case, when the amount of the phase transfer catalyst added is less than the above range, the reaction does not occur smoothly, and when it exceeds the above range, the production cost increases and there is no economy.

The acid used in the reaction is preferably sulfuric acid, hydrochloric acid, acetic acid, phosphoric acid, bromic acid, iodide, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, and the like. It is preferred to use 1 to 20 equivalents, most preferably 8 to 12 equivalents, based on the compound of formula (2). In this case, the amount of the acid added is less than the above range, the reaction does not occur smoothly, when the above amount is exceeded, the cost of production rises and there is no economic feasibility.

The hydroformylating agent used in the present invention is gas formaldehyde, formaldehyde solution, paraformaldehyde, trioxane, methal, etc., and the amount is 1.0 to 10.0 equivalents is used as the equivalent ratio with respect to the compound of formula 2 which is a starting material. It is preferable that it is 1-4 equivalents most preferably. In this case, the amount of the hydroformylating agent added is less than the above range, the reaction does not occur smoothly, if the above range is above the production cost rises and there is no economic efficiency.

Solvents used in the reaction include methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, benzene, toluene, xylene, acetonitrile, 1,4-dioxane, tetrahydrofuran, N, N-dimethylformamide, and the like. Organic solvents, or water and a mixed solvent of organic solvents and water, and even react in the absence of a solvent. The amount of the solvent to be used is preferably 0 to 50 equivalents, most preferably 10 to 20 equivalents based on the compound of formula (2) as the starting material. In this case, the amount of the solvent added is less than the above range, the reaction does not occur smoothly, when the amount exceeds the above range, the cost of production rises and there is no economic feasibility.

In the above reaction, the reaction temperature and the reaction time to be used are suitably about 2 to 30 hours in the range of 40 to 140 ° C, most preferably at 10 to 15 hours at 80 to 120 ° C. Although the temperature and time are determined to correlate with each other, the reaction does not occur smoothly below the above range, and when the above range is exceeded, the yield is lowered by the side reactants due to the side reaction.

When the reaction was completed, the compound of formula 1 produced was crystallized by adding a solvent in a conventional manner after extraction and concentration of the reaction solution, or pure target compound 2- (4-halomethylphenyl) propionic acid by the method of silica gel column chromatography. Can be obtained.

Compared with the conventional methods, the present invention provides a shorter reaction path than the conventional methods by reacting with a hydroformylating agent in the presence of halometal, a phase transfer catalyst, and an acid using an industrially available compound of formula (2). The advantage is that the desired compound can be prepared in high purity.

Hereinafter, the present invention will be described in detail by the following examples, but the present invention is not limited thereto.

(Example 1)

2-[(4-chloromethyl) phenyl] propionic acid

162 g of hydrochloric acid, 75 g of potassium chloride, 3 g of tetramethylammonium chloride, and 18 g of paraformaldehyde were sequentially added to 30 g of 2-phenylpropionic acid, and the mixture was reacted at 100 ° C for 12 hours, and then cooled to room temperature. 200 g of purified water and 200 g of ethyl acetate were added to the reaction solution, the organic layer was extracted, and concentrated. 250 g of nucleic acid was added thereto to crystallize, and the resulting crystals were filtered and dried to obtain 33.3 g of the target compound 2-[(4-chloromethyl) phenyl] propionic acid.

The yield was 84%, the purity measured by HPLC was 98.0%, and the results by NMR (CDCl ₃ , ppm) were 1.5 (3H, d), 3.7 (1H, q), 4.7 (2H, s ), 7.3 (4H, dd).

(Example 2)

2-[(4-bromomethyl) phenyl] propionic acid

To 30 g of 2-phenylpropionic acid, 94 g of water, 65 g of sulfuric acid, 98 g of sodium bromide, 3 g of tetradecyl trimethylammonium bromide, and 48 g of formalin were added sequentially, followed by reaction under heating to reflux for 10 hours, and then cooled to room temperature. 200 g of purified water and 250 g of ethyl acetate were added to the reaction solution, the organic layer was extracted, and concentrated. 220 g of nucleic acid was added thereto to crystallize, and the resulting crystals were filtered and dried to obtain 41.3 g of the target 2-[(4-bromomethyl) phenyl) propionic acid.

The yield was 85%, the purity measured by HPLC was 98.0%, the measurement results by NMR (CDCl ₃ , ppm) was 1.5 (3H, d), 3.7 (1H, q), 4.5 (2H, s ), 7.3 (4H, dd).

(Example 3)

2-[(4-iodomethyl) phenyl] propionic acid

To 30 g of 2-phenylpropionic acid, 30 g of dioxane, 35 g of water, 82 g of acetic acid, 150 g of sodium iodide, 3 g of hexadecyltrimethylammonium iodide, and 28 g of paraformaldehyde were added sequentially, followed by reaction at 100 ° C. for 10 hours, followed by cooling to room temperature. . 200 g of purified water and 250 g of ethyl acetate were added to the reaction solution, the organic layer was extracted, and concentrated. The mixture was separated by silica gel column chromatography, concentrated and dried to give 45.2 g of the target compound 2-[(4-iodomethyl) phenyl] propionic acid.

The yield was 78%, the purity measured by HPLC was 97.0%, and the results by NMR (CDCl ₃ , ppm) were 1.5 (3H, d), 3.7 (1H, q), 4.3 (2H, s ), 7.3 (4H, dd).

(Comparative Example 1)

2-[(4-chloromethyl) phenyl] propionic acid

10 g of anhydrous aluminum chloride and 25 g of tin chloride were added to 20 ml of chloroform, and cooled to -5 ° C, and then 9.5 g of methylal was added over 30 minutes. After adding 8.2 g of 2-phenylpropionic acid over 20 minutes at the same temperature, the internal temperature was raised to room temperature and stirred for 7 hours. 50 ml of ice water was added to the reaction solution, and after stirring, the organic layer was separated and washed in the order of constant, 5% sodium bicarbonate, and constant. The organic solvent was removed under reduced pressure, and then dried to obtain 3.5 g of the target compound 2-[(4-chloromethyl) phenyl] propionic acid.

The yield accordingly was 32% and the purity measured by HPLC was 83.2%.

(Comparative Example 2)

2-[(4-bromomethyl) phenyl] propionic acid

9.9 g of 2- (4-methylphenyl) propionic acid is dissolved in 100 ml of benzene, 13.9 g of N-bromosuccinimide and 0.2 g of active bromine are added and reacted under heating and reflux for about 7 hours. After the reaction was completed, the reaction temperature was cooled to room temperature, and the produced solid was removed by filtration. After the filtrate was removed under reduced pressure, 20 ml of a solution of n-nucleic acid and ethyl acetate in a ratio of 4: 1 was added and crystallized. The resulting crystals were filtered off and dried to obtain 9.8 g of the target product.

The yield was 61% and the purity as determined by HPLC was 87.4%.

As confirmed in the above-described examples and comparative examples, the high purity of 97-98% was obtained using the industrially available 2-phenylpropionic acid compound, which is 83.2% and 87.4% of the conventional method. In addition, it can be seen that the yield of the target compound is significantly improved from 32% and 61% of the conventional method with a high yield of 78 to 85%. Therefore, the method of the present invention can obtain a high purity target compound of high purity in a simpler process than the conventional method.

Claims (7)

A process for preparing 2- (4-halomethylphenyl) propionic acid of formula (I) comprising reacting 2-phenylpropionic acid of formula (2) with a halometal, a phase transfer catalyst, and a hydroformylating agent in the presence of an acid. [Formula 1] [Formula 2] Provided that X is selected from the group consisting of chlorine, bromine and iodine. The method of claim 1, wherein the halometal is selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium bromide, potassium bromide, calcium bromide, magnesium bromide, sodium iodide, potassium iodide, calcium iodide, and magnesium iodide, Its addition amount is 1 to 10 equivalents to the compound of Formula 2. The method of claim 1, wherein the phase transfer catalyst is selected from the group consisting of tetraethylammonium halide, benzyltrimethylammonium halide, tetradecyltrimethylammonium halide, tetrabutylammonium halide, and hexadecyltrimethylammonium halide, and an amount thereof is added to Chemical Formula 2 It is 0.01-2 equivalents with respect to the compound of. The method of claim 3, wherein the halide is selected from the group consisting of chlorine, bromine, and iodine. The method of claim 1, wherein the acid is selected from the group consisting of sulfuric acid, hydrochloric acid, acetic acid, phosphoric acid, bromic acid, iodic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, and formic acid, and the amount thereof is represented by Chemical Formula 2 It is 1-20 equivalents with respect to the compound of. The method of claim 1, wherein the hydroformylating agent is selected from the group consisting of gaseous formaldehyde, formaldehyde solution, paraformaldehyde, trioxane, and methal, the addition amount thereof is 1.0 to 10.0 as equivalent ratio to the compound of formula (2). The equivalent production method. The process according to claim 1, wherein the reaction is carried out in a range of 40 to 140 ° C. for about 2 to 30 hours.