KR20050043131A - Preparation method of 4-biphenylacetic acid - Google Patents

Abstract

The present invention relates to a process for preparing 4-biphenylacetic acid, and more particularly, (a) 4-aminophenylacetic acid of formula (2) by reducing 4-nitrophenylacetic acid of formula (1) in the presence of a palladium-carbon catalyst Manufacturing step; And (b) reacting 4-aminophenylacetic acid represented by the following Chemical Formula 2 with benzene to prepare 4-biphenylacetic acid represented by the following Chemical Formula 3 in the presence of sodium nitrite and an acid. It relates to a manufacturing method.

[Formula 1]

[Formula 2]

[Formula 3]

The method for producing 4-biacetic acid of the present invention has a simple manufacturing process and high purity and yield of 4-biphenylacetic acid.

Description

Production method of 4-biphenylacetic acid {PREPARATION METHOD OF 4-BIPHENYLACETIC ACID}

[Industrial use]

The present invention relates to a method for producing 4-biphenylacetic acid, and more particularly, to a method for producing 4-biphenylacetic acid, which has a simple manufacturing process and high yield and purity of 4-biphenylacetic acid.

[Prior art]

4-biphenylacetic acid is one of the medicines that are usefully used as anti-inflammatory drugs.

Representative methods of the 4-biphenyl acetic acid production method known to date are those described in Japanese Patent Laid-Open No. 62-45553 and Japanese Patent Laid-Open No. 62-45554, 4-phenylbenzaldehyde and 2-thioxo-4 Compound prepared by condensation reaction of -thiozolidinone (2-thioxo-4-thiazolidinone) or 2,4-imidazolidinone (2,4-imidazolidinone) was reduced from base to hydrogen peroxide to prepare 4-biphenylacetic acid. That's how.

However, if 4-biphenylacetic acid is prepared by the above method, it is required to go through several reaction stages, and various by-products are generated in each reaction stage. There is a problem that the yield and purity of the final product is low.

In order to solve the problems of the prior art, an object of the present invention is to provide a method for producing 4-biphenylacetic acid, which has a simple manufacturing process and high yield and purity of 4-biphenylacetic acid.

In order to achieve the above object, the present invention comprises the steps of (a) preparing 4-aminophenylacetic acid of formula (2) by reducing 4-nitrophenylacetic acid of formula (1) in the presence of a palladium-carbon catalyst; And (b) reacting 4-aminophenylacetic acid represented by the following Chemical Formula 2 with benzene to prepare 4-biphenylacetic acid represented by the following Chemical Formula 3 in the presence of sodium nitrite and an acid. It provides a manufacturing method.

[Formula 1]

[Formula 2]

[Formula 3]

Hereinafter, the present invention will be described in more detail.

First, the present invention prepares (4-) 4-aminophenylacetic acid of Chemical Formula 2 by reducing 4-nitrophenylacetic acid of Chemical Formula 1 with hydrogen gas in the presence of a palladium-carbon catalyst. This reaction mechanism is shown in Scheme 1 below.

Scheme 1

In Scheme 1, 4-nitrophenylacetic acid is preferably one that is dissolved by basifying with an inorganic base in water.

As the inorganic base, any of the inorganic bases generally used may be used, but among them, sodium hydroxide, potassium hydroxide and the like may be preferably used. The amount of the inorganic base used is preferably 1 to 2 equivalents.

The palladium-carbon catalyst used as the catalyst in Scheme 1 is preferably used 5 to 10%. In addition, the amount of the palladium-carbon catalyst used is preferably 1.5 to 3.5 g based on 100 g of 4-nitrophenylacetic acid of Chemical Formula 1. When the amount of the palladium-carbon catalyst used is less than 1.5 g with respect to 100 g of 4-nitrophenylacetic acid of Chemical Formula 1, Scheme 1 may not proceed smoothly. -The amount of carbon catalyst used is not economical disadvantages.

In Scheme 1, the pressure of the hydrogen gas used as the reducing agent of 4-nitrophenylacetic acid of Chemical Formula 1 is preferably 1 to 20 atm and more preferably 3 to 7 atm.

In addition, the reaction time of Scheme 1 is preferably 4 to 12 hours. This reaction time can be selected according to the amount of the palladium-carbon catalyst used.

In order to increase the yield and purity of the final product, the process of filtering and removing the palladium-carbon catalyst may be further performed after the completion of Scheme 1. In addition, a step of extracting 4-aminophenylacetic acid of Chemical Formula 2 by adding an acid to the reaction solution after the reaction of Scheme 1 may be further performed.

As the acid to be added at this time, any acid generally used may be used, but sulfuric acid, chloric acid, acetic acid and the like may be preferably used. In addition, the amount of acid added may be preferably used in 2 to 10 equivalents.

An extraction solvent is added to the reaction solution after the reaction in Scheme 1 to separate the organic layer containing 4-aminophenylacetic acid of the formula (2). When the separated organic layer is dried using magnesium sulfate or the like and filtered, 4-aminophenylacetic acid of Chemical Formula 2 having high purity is obtained.

The extraction solvent may be preferably used, such as benzene, ethyl acetate, ether, methylene chloride.

After passing through Scheme 1, (b) 4-biphenylacetic acid of Formula 3 is prepared by reacting 4-aminophenylacetic acid of Formula 2 prepared in Scheme 1 with benzene in the presence of sodium nitrite (NaNO ₂ ) and an acid. . The reaction mechanism is shown in Scheme 2 below.

Scheme 2

To the reaction filtrate containing 4-aminophenylacetic acid of Formula 2 prepared in Scheme 1, sodium nitrite, acid, and benzene were added to prepare a reaction solution, and then the temperature of the reaction solution was lowered.

The amount of sodium nitrite used in Scheme 2 is preferably 0.8 to 5 equivalents, more preferably 0.8 to 1.2 equivalents.

As the acid that can be used in Scheme 2, any acid generally used may be used, and chloric acid and acetic acid are preferable.

In addition, the amount of benzene added to Scheme 2 is preferably 1 to 50 equivalents, more preferably 10 to 20 equivalents.

In addition, the reaction temperature of Scheme 2 is preferably 0 to 10 ℃. This reaction temperature can be suitably adjusted with the quantity of sodium nitrite added.

If the amount of sodium nitrite exceeds 5 equivalents or the reaction temperature of reaction formula 2 exceeds 10 ° C., the reaction time is shortened, but the reaction proceeds too vigorously, and the reaction byproducts are excessively generated, resulting in a decrease in yield. Not.

After the reaction scheme 2, the reaction solution was separated by layer to obtain crystals to prepare 4-biphenylacetic acid of the present invention.

The overall reaction mechanism of the production method of 4-biphenylacetic acid of the present invention is shown in Scheme 3 below.

Scheme 3

As described above, the production method of 4-biphenyl acetic acid of the present invention is simple, and the yield and purity of 4-biphenyl acetic acid, which is the final target product prepared through the method, is high.

Hereinafter, preferred examples and comparative examples of the present invention are described. However, the following examples are only preferred embodiments of the present invention and the present invention is not limited to the following examples.

(Example 1)

After dissolving 4 g of sodium hydroxide in 90 g of distilled water, 18.1 g of 4-nitrophenylacetic acid was added to prepare a reaction solution, and the reaction solution was stirred. 0.36 g of 5% palladium-carbon was added to the reaction solution, and the reaction was carried out for 10 hours by pressurizing hydrogen at 5 atmospheres. After the reaction, 5% palladium-carbon was filtered using a filter coated with celite in the reaction solution.

12 ml of chloric acid and 6.9 g of sodium nitrite were sequentially added to the reaction solution which filtered the palladium-carbon from the reaction solution, and the temperature of the reaction solution was cooled to 5 ° C. 78 g of benzene was added to the reaction solution, and the mixture was stirred vigorously for 2 hours. When the reaction was completed, the reaction solution was separated by layers to separate the upper organic layer. The separated organic layer reaction solution was dried over magnesium sulfate and concentrated to prepare a concentrate. Addition of acetone to the concentrated solution and filtered on a filter paper and then crystallized to obtain 4-biphenyl-acetic acid 15.7 g (yield 74%) (m ?? p: . 166 ℃, IR: 1688 ㎝ -1, 1 H NMR: δ3 .7 (2H), δ7.3 to 7.9 (9H))

(Example 2)

After dissolving 4.4 g of sodium hydroxide in 90 g of distilled water, 18.1 g of 4-nitrophenylacetic acid was added to prepare a reaction solution, and the reaction solution was stirred. 0.36 g of 5% palladium-carbon was added to the reaction solution, and the reaction was carried out for 2 hours by pressurizing hydrogen at 10 atm. After the reaction, 5% palladium-carbon was filtered using a filter coated with celite in the reaction solution.

100 ml of benzene was added to the reaction solution to extract the organic layer. The organic layer was dried over magnesium sulfate, and the filtrate was collected, and 36 g of acetic acid and 6.9 g of sodium nitrite were sequentially added to the filtrate, and the reaction solution was cooled to 5 deg. 78 g of benzene was added to the reaction solution, and the mixture was stirred vigorously for 2 hours. When the reaction was completed, water was added and extracted to separate the upper organic layer. Water was added to the organic layer and the mixture was basified with 1N sodium hydroxide to separate the water layer. The water layer was separated and acidified slowly with dropwise addition of 4N chloric acid. The crystals produced at this time were filtered off. The filtered crystals were recrystallized in acetonitrile to give 14.5 g (69% yield) of 4-biphenylacetic acid.

(m ?? p: 166.5 ° C., IR: 1690 cm ^{−1, 1} H NMR: δ3.7 (2H), δ7.3 to 7.9 (9H))

(Comparative Example 1)

3 g of 3-biphenylaldehyde was dissolved in 4.8 ml of acetic anhydride. 2.4 g of 2-thioxo-4-thiazolidinone, 1.4 g of sodium acetate, and 20 ml of toluene were added and refluxed for 2 hours. Extracted with ether acetate, washed with water, dried and concentrated under reduced pressure to prepare 4.6 g (yield 94%) of 5- (4'-biphenylylmethylidene) -2-thioxo-4-thiazolidinone.

10 ml of 20% sodium hydroxide solution was added to 5- (4'-biphenylylmethylidene) -2-thioxo-4-thiazolidinone 3.0 and heated to reflux for 4 hours. The reaction solution was then cooled and washed with benzene. The water layer was acidified with hydrochloric acid and extracted with acetic acid ether. After extraction, the mixture was washed with water, saturated sodium chloride solution, and concentrated to prepare 1.3 g of 4-biphenylylpyruvic acid (yield 48%).

To 2.0 g of 4-biphenylylpyruvic acid, 15 ml of 0.5% sodium hydroxide solution and 4 ml of 30% hydrogen peroxide were added and stirred at 25 ° C for 4 hours. This solution was washed with toluene. The aqueous layer was acidified with hydrochloric acid and extracted with acetic acid ether. After extraction, water and saturated sodium chloride solution were washed sequentially and concentrated to prepare 1.5 g (yield 85%) of the target compound 4-biphenylacetic acid. This crystal was recrystallized in methyl ethyl ketone. The yield of 4-biphenylacetic acid prepared through the three step process was 38%.

(Evaluation)

As shown in Examples 1 to 2 and Comparative Example 1, when 4-biphenyl acetic acid was prepared through the 4-biphenyl acetic acid production method of Examples 1 to 2, the yields of the final products were 74% and 69%, respectively. By the method of Comparative Example 1, the yield was almost doubled compared to the yield (38%) when 4-biphenylacetic acid was prepared.

As mentioned above, the manufacturing method of 4-biphenyl acetic acid of this invention is simple in a manufacturing process, and the purity and yield of 4-vinyl acetic acid are high.

Claims (1)

(a) preparing 4-aminophenylacetic acid of formula (2) by reducing 4-nitrophenylacetic acid of formula (1) in the presence of a palladium-carbon catalyst; And (b) reacting 4-aminophenylacetic acid of Chemical Formula 2 prepared above with benzene in the presence of sodium nitrite and an acid to prepare 4-biphenylacetic acid of Chemical Formula 3 4-biphenylphenylacetic acid production method comprising a. [Formula 1] [Formula 2] [Formula 3]